Biological implications of differential expression of mitochondrial-shaping proteins in Parkinson’s disease

an ioxidan s A icle Biological Implica ions o Di e en ial Exp ession o Mi ochond ial-Shaping P o eins in Pa kinson’s Disease Sa a Rocha 1,2,†, Ana F ei as 1,3,4,†, So ia C. Guima aes 1,3, Rui Vi o ino 5,6 ID , Miguel A oso 1,3 and Ma ia Gomez-Laza o 1,3,*ID 1i3S—Ins i u o de In es igação e Ino ação em Saúde, Uni e sidade do Po o, 4200-135 Po o, Po ugal; [email p o ec ed] (S.R.); ana [email p o ec ed] (A.F.); [email p o ec ed] (S.C.G.); [email p o ec ed] (M.A.) 2IBMC—Ins i u o de Biologia Molecula e Celula , Uni e sidade do Po o, 4200-135 Po o, Po ugal 3INEB—Ins i u o de Engenha ia Biomédica, Uni e sidade do Po o, 4200-135 Po o, Po ugal 4FMUP—Faculdade de Medicina da Uni e sidade do Po o, 4200-319 Po o, Po ugal 5 iBiMED, Depa men o Medical Sciences, Uni e si y o A ei o, 3810-193 A ei o, Po ugal; [email p o ec ed] 6Unidade de In es igação Ca dio ascula , Depa amen o de Ci u gia e Fisiologia, Uni e sidade do Po o, 4200-319 Po o, Po ugal *Co espondence: [email p o ec ed]; Tel.: +351-220-408-815 † These au ho s con ibu ed equally o his wo k. Recei ed: 28 No embe 2017; Accep ed: 14 Decembe 2017; Published: 21 Decembe 2017 Abs ac : I has long been accep ed ha mi ochond ial unc ion and mo phology is a ec ed in Pa kinson’s disease, and ha mi ochond ial unc ion can be di ec ly ela ed o i s mo phology. So a , mi ochond ial mo phological al e a ions s udies, in he con ex o his neu odegene a i e disease, ha e been pe o med h ough mic oscopic me hodologies. The goal o he p esen wo k is o add ess i he modi ica ions in he mi ochond ial-shaping p o eins occu ing in his diso de ha e implica ions in o he cellula pa hways, which migh cons i u e impo an pa hways o he disease p og ession. To do so, we conduc ed a no el app oach h ough a ho ough explo a ion o he a ailable p o eomics-based s udies in he con ex o Pa kinson’s disease. The analysis p o ided insigh in o he al e ed biological pa hways a ec ed by changes in he exp ession o mi ochond ial-shaping p o eins ia di e en bioin o ma ic ools. Unexpec edly, we obse ed ha he mi ochond ial-shaping p o eins al e ed in he con ex o Pa kinson’s disease a e, in he as majo i y, ela ed o he o ganiza ion o he mi ochond ial c is ae. Con e sely, in he s udies ha ha e eso ed o mic oscopy-based echniques, he mos widely epo ed al e a ion in he con ex o his diso de is mi ochond ia agmen a ion. C is ae memb ane o ganiza ion is pi o al o mi ochond ial ATP p oduc ion, and changes in hei mo phology ha e a di ec impac on he o ganiza ion and unc ion o he oxida i e phospho yla ion (OXPHOS) complexes. To unde s and which biological p ocesses a e a ec ed by he al e a ion o hese p o eins we analyzed he binding pa ne s o he mi ochond ial-shaping p o eins ha we e ound al e ed in Pa kinson’s disease. We showed ha he binding pa ne s all in o se en di e en cellula componen s, which include mi ochond ia, p o easome, and endoplasmic e iculum (ER), amongs o he s. I is no ewo hy ha , by e alua ing he biological p ocess in which hese modi ied p o eins a e in ol ed, we showed ha hey a e ela ed o he p oduc ion and me abolism o ATP, immune esponse, cy oskele on al e a ion, and oxida i e s ess, amongs o he s. In summa y, wi h ou bioin o ma ics app oach using he da a on he modi ied p o eins in Pa kinson’s disease pa ien s, we we e able o ela e he al e a ion o mi ochond ial-shaping p o eins o modi ica ions o c ucial cellula pa hways a ec ed in his disease. Keywo ds: Pa kinson’s disease; p o eomics; bioin o ma ics; biological p ocesses; mi ochond ia An ioxidan s 2018,7, 1; doi:10.3390/an iox7010001 www.mdpi.com/jou nal/an ioxidan s An ioxidan s 2018,7, 1 2 o 45 1. In oduc ion Mi ochond ia a e pi o al o ganelles o se e al cellula unc ions, namely, he p oduc ion o ATP h ough oxida i e phospho yla ion, he egula ion o he K ebs cycle, a y acid me abolism, gluconeogenesis, heme-syn hesis, calcium and edox homeos asis, cell signaling, and he ampli ica ion o apop osis [ 1 ]. They a e highly dynamic o ganelles, as hey can change hei shape in esponse o cellula s imuli by usion and ission p ocesses and by hei mo emen along he cellula cy oskele on [ 2 ]. Al e a ions o mi ochond ia mo phology can signi ican ly in luence se e al unc ions o he cellula me abolism, no only ela ed o ene gy p oduc ion bu also in communica ion wi h he cy osol and he impo and expo o p o eins, lipids, solu es, and me aboli es o e en he cy osol p o ec ion om possible ha m ul e ec s o ce ain mi ochond ial componen s [ 3 ]. Mi ochond ia dynamic p ocesses a e o u mos impo ance o he mi ochond ial g ow h a e, hei edis ibu ion wi hin he cell, and o he main enance o heal hy mi ochond ia and p ope unc ioning hence hei al e a ions a e equen ly associa ed wi h di e en pa hological condi ions [4]. Pa kinson’s disease is a highly debili a ing condi ion, being a common neu odegene a i e disease, and mo e han 10 million people wo ldwide a e a ec ed by his disease [ 5 ]. Cu en ly, i s e iology is no ully un a eled; howe e , e idences poin o he impo ance o mi ochond ia in i s pa hobiology. Clinical ea u es include mainly mo o -based dys unc ions such as b adykinesia, es ing emo , o cogwheel igidi y [ 6 ]. Those ea u es a e a consequence o he loss o dopamine gic (DA) neu ons in he subs an ia nig a (SN). The associa ion be ween mi ochond ial dys unc ion and he pa hobiology o Pa kinson’s disease was i s desc ibed in 1989. By using pos mo em issue om human pa ien s, a unc ional de iciency was ound on he mi ochond ial Complex I om he espi a o y chain [ 7 , 8 ]. Accumula ing e idence shows he occu ence o mi ochond ia agmen a ion in he con ex o di e en models o he pa hology. Fu he mo e, al e a ion o he exp ession le els o di e en p o eins linked o Pa kinson ´ s disease (e.g., PINK1, Pa kin, o DJ-1) a e known o induce mi ochond ia agmen a ion in DA neu ons [ 9 , 10 ]. Recen ly, i was obse ed ha al e a ions o he mi ochond ial mo phology can be ela ed o hei unc ional s a e and new ools we e consequen ly designed o analyze mi ochond ial shape and p edic mi ochond ial unc ion [11]. In e es ingly, se e al hypo heses o he speci ic loss o he DA neu ons om he SN a e also ela ed o he ulne abili y associa ed wi h he mi ochond ia o hese neu ons [ 12 ]. I has been sugges ed ha DA neu ons om he SN a e mo e suscep ible o oxida i e s ess due o he p oduc ion o eac i e oxygen species (ROS) du ing dopamine deg ada ion, and hese neu ons p esen ewe amoun s o an ioxidan s han o he DA neu ons wi hin he b ain [ 12 ]. They ha e e y long axons in which mi ochond ia a el and also agmen o be able o accommoda e wi hin he synap ic e minals. Besides, i is known ha DA neu ons om he SN p esen lowe mi ochond ia mass in he soma han in he dend i es, indica ing ha al e a ions o ei he agmen a ion o mo emen along he cy oskele on migh ha e a bigge impac on hese neu ons [ 12 ]. Addi ionally, mos o he subs ances ha a e used o model he disease di ec ly a ge he mi ochond ia and induce he speci ic degene a ion o he DA neu ons. In his s udy we made a ho ough li e a u e sea ch o iden i y he mi ochond ial p o eins in ol ed in con olling mi ochond ial mo phology ha a e di e en ially exp essed in Pa kinson’s disease. The al e ed biological pa hways ha migh be a ec ed by changes in he exp ession o hese mi ochond ial-shaping p o eins in Pa kinson’s disease we e iden i ied and analyzed. Conside a ions we e made o be e unde s and he biological mechanisms in ol ed in his debili a ing disease. 2. Me hods Li e a u e Sea ch Fo he compila ion o he mi ochond ial p o eins in ol ed in con olling mi ochond ial mo phology (Table 1), wo independen use s pe o med a sea ch on PubMed, Science Di ec , and Google up o 7 July 2017 using he ollowing keywo ds in sepa a e que ies: “mi ochond ial mo phology”, “mi ochond ial shape”, “mi ochond ial o ganiza ion”, “mi ochond ial usion”, “mi ochond ial ission”, and “mi ochond ial dynamics”. Only Homo sapiens p o eins we e ga he ed. The co esponding gene name and synonyms we e collec ed in Table 1by sea ching a he Uni e sal P o ein Resou ce (UniP o ) da abases [13]. An ioxidan s 2018,7, 1 3 o 45 Table 1. Lis o mi ochond ial-shaping p o eins. Gene Name (wi h Synonyms) P o ein Name Func ion Localiza ion Shaping Func ion Re e ences APOO, FAM121B, MIC23, MIC26, My025, UNQ1866/PRO4302 MICOS Complex subuni MIC26 (Apolipop o ein O) (MICOS Complex subuni MIC23) (P o ein FAM121B) Componen o he MICOS Complex, a la ge p o ein Complex o he inne mi ochond ial memb ane ha plays c ucial oles in he main enance o c is a junc ions, inne memb ane a chi ec u e, and o ma ion o con ac si es o he ou e memb ane IMM C is ae shape [14–16] APOOL, CXo 33, FAM121A, MIC27, UNQ8193/PRO23204 MICOS Complex subuni MIC27 (Apolipop o ein O-like) (P o ein FAM121A) Componen o he MICOS Complex, a la ge p o ein Complex o he inne mi ochond ial memb ane ha plays c ucial oles in he main enance o c is a junc ions, inne memb ane a chi ec u e, and o ma ion o con ac si es o he ou e memb ane IMM C is ae shape [14,15,17,18] ATP5A1, ATP5B, ATP5C1, ATP5D, ATP5E, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5H, ATP5I, ATP5J, ATP5J2, ATP5L, ATP5O, MT-ATP6, MT-ATP8 ATP syn hase ATP p oduc ion IMM C is ae shape [3,15,19] ATPIF1, ATPI ATPase inhibi o , mi ochond ial (Inhibi o o F(1)F(o)-ATPase) (IF(1)) (IF1) ATP p oduc ion egula ion Ma ix C is ae shape [3,20] BAK1, BAK, BCL2L7, CDN1 Bcl-2 homologous an agonis /kille (Apop osis egula o BAK) P omo es apop osis OMM OMM pe meabiliza ion [3,21] BAX, BCL2L4 Apop osis egula o BAX Accele a es apop osis OMM OMM pe meabiliza ion [3,19,21,22] BCL2 Apop osis egula o Bcl-2 P omo es cell su i al OMM OMM pe meabiliza ion [3,22] BCL2A1, BCL2L5, BFL1, GRS, HBPA1 Bcl-2- ela ed p o ein A1 (A1-A) (Hemopoie ic-speci ic ea ly esponse p o ein) (P o ein BFL-1) P omo es cell su i al OMM No clea unc ion [23,24] BCL2L11, BIM Bcl-2-like p o ein 11 (Bcl2-L-11) (Bcl2-in e ac ing media o o cell dea h) Induces apop osis and anoikis IMM C is ae emodeling [25,26] BID BH3-in e ac ing domain dea h agonis The majo p o eoly ic p oduc p15 BID allows he elease o cy och ome c IMM C is ae emodeling [25,27] BIK, NBK Bcl-2-in e ac ing kille (Apop osis induce NBK) (BIP1) (BP4) P omo es apop osis IMM C is ae emodeling [25,28] CHCHD3, MIC19, MINOS3 MICOS Complex subuni MIC19 (Coiled-coil-helix-coiled-coil-helix domain-con aining p o ein 3) Componen o he MICOS Complex, a la ge p o ein Complex o he inne mi ochond ial memb ane ha plays c ucial oles in he main enance o c is a junc ions, inne memb ane a chi ec u e, and o ma ion o con ac si es o he ou e memb ane IMM C is ae shape [14,16,18] An ioxidan s 2018,7, 1 4 o 45 Table 1. Con . Gene Name (wi h Synonyms) P o ein Name Func ion Localiza ion Shaping Func ion Re e ences COA3, CCDC56, MITRAC12, HSPC009 Cy och ome c oxidase assembly ac o 3 homolog, mi ochond ial (Coiled-coil domain-con aining p o ein 56) (Mi ochond ial ansla ion egula ion assembly in e media e o cy och ome c oxidase p o ein o 12 kDa) Co e componen o he MITRAC (mi ochond ial ansla ion egula ion assembly in e media e o cy och ome c oxidase) Complex, which egula es cy och ome c oxidase assembly. IMM Cy och ome c oxidase [29,30] COX4I1, COX4I2, COX5A, COX5B, COX6A1, COX6A2, COX6B1, COX6B2, COX6C, COX7A1, COX7A2, COX7B, COX7B2, COX7C, COX8A, COX8C, MT-CO1, MT-CO2, MT-CO3 Mi ochond ial Complex IV: cy och ome c oxidase subuni s ATP p oduc ion IMM C is ae shape [18] CYC1, MT-CYB, UQCR10, UQCR11, UQCRB, UQCRC1, UQCRC2, UQCRFS1, UQCRH, UQCRQ Mi ochond ial Complex III: ubiquinol-cy och ome c educ ase Complex subuni s (UQCR) ATP p oduc ion IMM C is ae shape [18] DNAJC19, TIM14, TIMM14 Mi ochond ial impo inne memb ane anslocase subuni TIM14 (DnaJ homolog sub amily C membe 19) P obable componen o he PAM Complex, a Complex equi ed o he ansloca ion o ansi pep ide-con aining p o eins om he inne memb ane in o he mi ochond ial ma ix in an ATP-dependen manne IMM C is a shape [15,31,32] DNM1L, DLP1, DRP1 Dynamin-1-like p o ein (EC 3.6.5.5) (Dnm1p/Vps1p-like p o ein) (DVLP) (Dynamin amily membe p oline- ich ca boxyl- e minal domain less) (Dymple) (Dynamin-like p o ein) (Dynamin-like p o ein 4) (Dynamin-like p o ein IV) (HdynIV) (Dynamin- ela ed p o ein 1) Mi ochond ial and pe oxisome di ision OMM and cy osol Fission [3,18,22] DNM2, DYN2 Dynamin-2 (EC 3.6.5.5) Mic o ubule-associa ed o ce-p oducing p o ein in ol ed in p oducing mic o ubule bundles and able o bind and hyd olyze GTP Cy osol Fission [4,33] FIS1, TTC11, CGI-135 Mi ochond ial ission 1 p o ein (FIS1 homolog) (hFis1) (Te a icopep ide epea p o ein 11) (TPR epea p o ein 11) Mi ochond ial agmen a ion OMM Fission [3,19,22] FUNDC1 FUN14 domain-con aining p o ein 1FUN14 domain-con aining p o ein 1 Mi ophagy OMM Fission [29,34–36] GDAP1 Ganglioside-induced di e en ia ion-associa ed p o ein 1 Mi ochond ial ission OMM Fission [1,19,22] h zo1 Mi ochond ial ansmemb ane GTPase Fzo-1 FUNDC1 media es highly selec i e mi ochond ial clea ance unde hypoxic condi ions wi hou impac ing gene al au ophagy OMM Fusion [19] An ioxidan s 2018,7, 1 5 o 45 Table 1. Con . Gene Name (wi h Synonyms) P o ein Name Func ion Localiza ion Shaping Func ion Re e ences IMMT, HMP, MIC60, MINOS2, PIG4, PIG52 MICOS Complex subuni MIC60(Cell p oli e a ion-inducing gene 4/52 p o ein) (Inne mi ochond ial memb ane p o ein) (Mi o ilin) (p87/89) Componen o he MICOS Complex, a la ge p o ein Complex o he inne mi ochond ial memb ane ha plays c ucial oles in he main enance o c is a junc ions, inne memb ane a chi ec u e, and o ma ion o con ac si es o he ou e memb ane IMM C is ae shape [15,16,18,19,37] INF2, C14o 151, C14o 173 In e ed o min-2 (HBEBP2-binding p o ein C) Se e s ac in ilamen s and accele a es hei polyme iza ion and depolyme iza ion Cy osol Mi ochond ial cons ic ion [29,38] LETM1 Mi ochond ial p o on/calcium exchange p o ein (Leucine zippe -EF-hand-con aining ansmemb ane p o ein 1) Mi ochond ial p o on/calcium an ipo e ha media es p o on-dependen calcium e lux om mi ochond ia IMM Fission [1,22,39] MARCH5, RNF153 E3 ubiqui in-p o ein ligase MARCH5 (EC 2.3.2.27) (Memb ane-associa ed RING inge p o ein 5) (Memb ane-associa ed RING-CH p o ein V) (MARCH-V) (Mi ochond ial ubiqui in ligase) (MITOL) (RING inge p o ein 153) (RING- ype E3 ubiqui in ans e ase MARCH5) Memb ane-bound E3 ligase o mi ochond ial mo phology con ol OMM Fission [1,19] MAVS, IPS1, KIAA1271, VISA Mi ochond ial an i i al-signaling p o ein (MAVS) (CARD adap e inducing in e e on be a) (Ca di ) (In e e on be a p omo e s imula o p o ein 1) (IPS-1) (Pu a i e NF-kappa-B-ac i a ing p o ein 031N) (Vi us-induced-signaling adap e ) (VISA) Requi ed o inna e immune esponse agains i uses OMM Fusion [22,40] MCL1, BCL2L3 Induced myeloid leukemia cell di e en ia ion p o ein Mcl-1 (Bcl-2-like p o ein 3) (Bcl2-L-3) (Bcl-2- ela ed p o ein EAT/mcl1) (mcl1/EAT) Regula ion o apop osis IMM and OMM C is ae shape (IMM iso o m) [18,29,41,42] MFF, C2o 33, AD030, AD033, GL004 Mi ochond ial Fission Fac o Mi ochond ial and pe oxisome di ision OMM Fission [3,19] MFN1 Mi o usin-1 (EC 3.6.5.-) (Fzo homolog) (T ansmemb ane GTPase MFN1) Mi ochond ial usion OMM Fusion [18,22,43] MFN2, CPRP1, KIAA0214 Mi o usin-2 (EC 3.6.5.-) (T ansmemb ane GTPase MFN2) Regula es mi ochond ial clus e ing and usion OMM Fusion [18,22,43] MIC13, C19o 70, QIL1 MICOS Complex subuni MIC13 (P o ein P117) Componen o he MICOS Complex, a la ge p o ein Complex o he inne mi ochond ial memb ane ha plays c ucial oles in he main enance o c is a junc ions, inne memb ane a chi ec u e, and o ma ion o con ac si es o he ou e memb ane IMM C is ae shape [15,18] MIEF1, MID51, SMCR7L Mid51/Mie , mi ochond ial dynamics p o eins o 51 Componen o he MICOS Complex, a la ge p o ein Complex o he inne mi ochond ial memb ane ha plays c ucial oles in he main enance o c is a junc ions, inne memb ane a chi ec u e, and o ma ion o con ac si es o he ou e memb ane OMM Fission [3,19] An ioxidan s 2018,7, 1 6 o 45 Table 1. Con . Gene Name (wi h Synonyms) P o ein Name Func ion Localiza ion Shaping Func ion Re e ences MIEF2, MID49, SMCR7 Mi ochond ial dynamics p o ein MID49 (Mi ochond ial dynamics p o ein o 49 kDa) (Mi ochond ial elonga ion ac o 2) (Smi h-Magenis synd ome ch omosomal egion candida e gene 7 p o ein) Componen o he MICOS Complex, a la ge p o ein Complex o he inne mi ochond ial memb ane ha plays c ucial oles in he main enance o c is a junc ions, inne memb ane a chi ec u e, and o ma ion o con ac si es o he ou e memb ane OMM Fission [3,19] MIGA1, FAM73A Mi ogua din 1 (P o ein FAM73A) Regula o o mi ochond ial usion OMM Fusion [4,44] MIGA2, C9o 54, FAM73B, PSEC0112 Mi ogua din 2 (P o ein FAM73B) Regula o o mi ochond ial usion OMM Fusion [4,44] MINOS1, C1o 151, MIC10 MICOS Complex subuni MIC10 (Inne mi ochond ial memb ane o ganizing sys em p o ein 1) Main enance o c is ae junc ions, inne memb ane a chi ec u e, and o ma ion o con ac si es o he ou e memb ane IMM C is ae shape [15,18] MTFP1, MTP18, HSPC242, My022 Mi ochond ial ission p ocess p o ein 1(Mi ochond ial 18 kDa p o ein) (MTP18) In ol ed in he mi ochond ial di ision p obably by egula ing memb ane ission IMM Fission [1,22,45] MUL1, C1o 166, GIDE, MAPL, MULAN, RNF218 Mi ochond ial ubiqui in ligase ac i a o o NFKB 1 (EC 2.3.2.27) (E3 SUMO-p o ein ligase MUL1) (E3 ubiqui in-p o ein ligase MUL1) (G ow h inhibi ion and dea h E3 ligase) (Mi ochond ial-ancho ed p o ein ligase) (MAPL) (Pu a i e NF-kappa-B-ac i a ing p o ein 266) (RING inge p o ein 218) (RING- ype E3 ubiqui in ans e ase NFKB 1) Ubiqui in ligase ac i i y OMM Fusion [19,29] NFE2L2, NRF2 Nuclea ac o e y h oid 2- ela ed ac o 2 (NF-E2- ela ed ac o 2) (NFE2- ela ed ac o 2) (HEBP1) (Nuclea ac o , e y h oid de i ed 2, like 2) T ansc ip ion ac i a o ha binds o an ioxidan esponse (ARE) elemen s in he p omo e egions o a ge genes Cy osol Fusion [29,46,47] NRF1 Nuclea espi a o y ac o 1 (NRF-1) (Alpha palind omic-binding p o ein) (Alpha-pal) T ansc ip ion ac o implica ed in he con ol o nuclea genes equi ed o espi a ion, heme biosyn hesis, and mi ochond ial DNA ansc ip ion and eplica ion Cy osol Fission [29,46,48,49] OMA1, MPRP1 Me alloendopep idase OMA1, mi ochond ial (EC 3.4.24.-) (Me allop o ease- ela ed p o ein 1) (MPRP-1) (O e lapping wi h he m-AAA p o ease 1 homolog) Me allop o ease ha is pa o he quali y con ol sys em in he inne memb ane o mi ochond ia IMM Fusion [1,19] OPA1, KIAA0567 Dynamin-like 120 kDa p o ein, mi ochond ial (EC 3.6.5.5) (Op ic a ophy p o ein 1) (Clea ed in o: Dynamin-like 120 kDa p o ein, o m S1) Opa1 media es dynamics changes in c is ae mo phology ha co ela e wi h he me abolic s a e o he o ganelle IMM C is ae shape, usion [1,3,15,18,22,50] PARL, PSARL, PRO2207 P esenilins-associa ed homboid-like p o ein, mi ochond ial (EC 3.4.21.105) (Mi ochond ial in amemb ane clea ing p o ease PARL) (Clea ed in o: P-be a (Pbe a)) Requi ed o he con ol o apop osis IMM Mi ochond ial mo phology [1,51] An ioxidan s 2018,7, 1 7 o 45 Table 1. Con . Gene Name (wi h Synonyms) P o ein Name Func ion Localiza ion Shaping Func ion Re e ences PGAM5 Se ine/ h eonine-p o ein phospha ase PGAM5, mi ochond ial (EC 3.1.3.16) (Bcl-XL-binding p o ein 68) (Phosphoglyce a e mu ase amily membe 5) Displays phospha ase ac i i y o se ine/ h eonine esidues, as well as dephospho yla es and ac i a es MAP3K5 kinase OMM Fission [1,29,52] PHB P ohibi in P ohibi in inhibi s DNA syn hesis; i has a ole in egula ing p oli e a ion IMM C is ae shape [1,15,18,31,53] PHB2, BAP, REA P ohibi in-2 (B-cell ecep o -associa ed p o ein BAP37) (D-p ohibi in) (Rep esso o es ogen ecep o ac i i y) Ac s as a media o o ansc ip ional ep ession by nuclea ho mone ecep o s ia he ec ui men o his one deace ylases (by simila i y); unc ions as an es ogen ecep o (ER)-selec i e co egula o ha po en ia es he inhibi o y ac i i ies o an ies ogens and ep esses he ac i i y o es ogens IMM C is ae shape [1,15,18] PINK1 Se ine/ h eonine-p o ein kinase PINK1, mi ochond ial (EC 2.7.11.1) (BRPK) (PTEN-induced pu a i e kinase p o ein 1) P o ec s agains mi ochond ial dys unc ion du ing cellula s ess by phospho yla ing mi ochond ial p o eins OMM Fission [1,54] PLD6 Mi ochond ial ca diolipin hyd olase (EC 3.1.-.-) (Choline phospha ase 6) (Mi ochond ial phospholipase) (Mi oPLD) (Phospha idylcholine-hyd olyzing phospholipase D6) (Phospholipase D6) (PLD 6) (P o ein zucchini homolog) P oposed o ac as a ca diolipin hyd olase o gene a e phospha idic acid a he mi ochond ial su ace OMM Fusion [4,19,22,45] PPARGC1A, LEM6, PGC1, PGC1A, PPARGC1 Pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-alpha (PGC-1-alpha) (PPAR-gamma coac i a o 1-alpha) (PPARGC-1-alpha) (Ligand e ec modula o 6) T ansc ip ional coac i a o o s e oid ecep o s and nuclea ecep o s Cy oplasm and nucleus Fusion [29,49,55] PPARGC1B, PERC, PGC1, PGC1B, PPARGC1 Pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-be a (PGC-1-be a) (PPAR-gamma coac i a o 1-be a) (PPARGC-1-be a) (PGC-1- ela ed es ogen ecep o alpha coac i a o ) Plays he ole o s imula o o ansc ip ion ac o s and nuclea ecep o s ac i i ies Nucleus Fusion [29,55,56] PRELID1, PRELI, CGI-106, SBBI12 PRELI domain-con aining p o ein 1, mi ochond ial (25 kDa p o ein o ele an e olu iona y and lymphoid in e es ) (Px19-like p o ein) In ol ed in he modula ion o he mi ochond ial apop o ic pa hway by ensu ing he accumula ion o ca diolipin (CL) in mi ochond ial memb anes In e memb ane space Fission [57,58] PRKN, PARK2 E3 ubiqui in-p o ein ligase pa kin (Pa kin) (EC 2.3.2.-) (Pa kin RBR E3 ubiqui in-p o ein ligase) (Pa kinson ju enile disease p o ein 2) (Pa kinson disease p o ein 2) Func ions wi hin a mul ip o ein E3 ubiqui in ligase Complex, ca alyzing he co alen a achmen o ubiqui in moie ies on o subs a e p o eins Cy osol and mi ochond ia Fission [1,54,59,60] ROMO1, C20o 52 Reac i e oxygen species modula o 1(ROS modula o 1) (Epididymis issue p o ein Li 175) (Gly ichin) (Mi ochond ial a ge ing GxxxG mo i p o ein) (MTGM) (P o ein MGR2 homolog) Induces he p oduc ion o eac i e oxygen species (ROS), which a e necessa y o cell p oli e a ion IMM Fusion [29,61] An ioxidan s 2018,7, 1 8 o 45 Table 1. Con . Gene Name (wi h Synonyms) P o ein Name Func ion Localiza ion Shaping Func ion Re e ences SAMM50, SAM50, CGI-51, TRG3 So ing and assembly machine y componen 50 homolog (T ans o ma ion- ela ed gen 3 p o ein) (TRG-3) Plays a c ucial ole in he main enance o he s uc u e o mi ochond ial c is ae and he p ope assembly o he mi ochond ial espi a o y chain Complexes OMM C is ae shape [18] SH3GLB1, KIAA0491, CGI-61 Endophilin-B1 (Bax-in e ac ing ac o 1) (Bi -1) (SH3 domain-con aining GRB2-like p o ein B1) Ou e mi ochond ial dynamics OMM OMM pe meabili y [1,22,62] SH3GLB2, KIAA1848, PP578 Endophilin-B2 (SH3 domain-con aining GRB2-like p o ein B2) Mi ophagy Cy osol Fission [63] SLC25A10, DIC Mi ochond ial dica boxyla e ca ie (Solu e ca ie amily 25 membe 10) In ol ed in he ansloca ion o malona e, mala e, and succina e in exchange o phospha e, sul a e, sul i e, o hiosul a e ac oss he inne mi ochond ial memb ane IMM C is ae shape [18,50] SLC25A11, SLC20A4 Mi ochond ial 2-oxoglu a a e/mala e ca ie p o ein (OGCP) (Solu e ca ie amily 25 membe 11) Ca alyzes he anspo o 2-oxoglu a a e ac oss he inne mi ochond ial memb ane in an elec oneu al exchange o mala e o o he dica boxylic acids, and plays an impo an ole in se e al me abolic p ocesses, including he mala e-aspa a e shu le, he oxoglu a a e/isoci a e shu le, in gluconeogenesis om lac a e, and in ni ogen me abolism IMM C is ae shape [18,50] SLC25A12, ARALAR1 Calcium-binding mi ochond ial ca ie p o ein A ala 1 (Mi ochond ial aspa a e glu ama e ca ie 1) (Solu e ca ie amily 25 membe 12) Ca alyzes he calcium-dependen exchange o cy oplasmic glu ama e wi h mi ochond ial aspa a e ac oss he inne mi ochond ial memb ane; may ha e a unc ion in he u ea cycle IMM C is ae shape [18,50] SLC25A13, ARALAR2 Calcium-binding mi ochond ial ca ie p o ein A ala 2 (Ci in) (Mi ochond ial aspa a e glu ama e ca ie 2) (Solu e ca ie amily 25 membe 13) Ca alyzes he calcium-dependen exchange o cy oplasmic glu ama e wi h mi ochond ial aspa a e ac oss he inne mi ochond ial memb ane; may ha e a unc ion in he u ea cycle IMM C is ae shape [18,50] SLC25A38 Solu e ca ie amily 25 membe 38, Appop osin Mi ochond ial impo machine y IMM Fusion [29,64] SMAD2, MADH2, MADR2 Mo he s agains decapen aplegic homolog 2 (MAD homolog 2) (Mo he s agains DPP homolog 2) (JV18-1) (Mad- ela ed p o ein 2) (hMAD-2) (SMAD amily membe 2) (SMAD 2) (Smad2) (hSMAD2) Recep o - egula ed SMAD (R-SMAD) ha is an in acellula signal ansduce and ansc ip ional modula o ac i a ed by TGF-be a ( ans o ming g ow h ac o ) and ac i in ype 1 ecep o kinases Cy osol Fusion [29,65] SPG7, CAR, CMAR, PGN Pa aplegin (EC 3.4.24.-) (Cell ma ix adhesion egula o ) (Spas ic pa aplegia 7 p o ein) ATP-dependen zinc me allop o ease IMM C is ae shape [18] SPG7, CAR, CMAR, PGN Pa aplegin (EC 3.4.24.-) (Cell ma ix adhesion egula o ) (Spas ic pa aplegia 7 p o ein) ATP-dependen zinc me allop o ease IMM Fusion [1,22,51] An ioxidan s 2018,7, 1 9 o 45 Table 1. Con . Gene Name (wi h Synonyms) P o ein Name Func ion Localiza ion Shaping Func ion Re e ences STOML2, SLP2, HSPC108 S oma in-like p o ein 2, mi ochond ial(SLP-2) (EPB72-like p o ein 2) (Pa ap o ein a ge 7) (Pa a a g-7) Mi ochond ial p o ein ha p obably egula es he biogenesis and he ac i i y o mi ochond ia; s imula es ca diolipin biosyn hesis, binds ca diolipin-en iched memb anes whe e i ec ui s and s abilizes some p o eins including p ohibi in, and may he e o e ac in he o ganiza ion o unc ional mic odomains in mi ochond ial memb anes IMM C is ae shape/S abilize IM s uc u e [15,18] SYNJ2, KIAA0348 Synap ojanin-2(EC 3.1.3.36) (Synap ic inosi ol 1,4,5- isphospha e 5-phospha ase 2) Memb ane a icking and signaling ansduc ion Cy osol Mi ochond ial agg ega ion [66] TAZ, EFE2, G4.5 Ta azzin (P o ein G4.5) Some iso o ms may be in ol ed in ca diolipin (CL) me abolism OMM C is ae shape [15,16,67,68] TFAM, TCF6, TCF6L2 T ansc ip ion ac o A, mi ochond ial (m TFA) (Mi ochond ial ansc ip ion ac o 1) (M TF1) (T ansc ip ion ac o 6) (TCF-6) (T ansc ip ion ac o 6-like 2) Binds o he mi ochond ial ligh s and p omo e and unc ions in mi ochond ial ansc ip ion egula ion Ma ix Mi ochond ial biogenesis [29,46] TRAK1, KIAA1042, OIP106 T a icking kinesin-binding p o ein 1 (106 kDa O-GlcNAc ans e ase-in e ac ing p o ein) O ganelle a icking OMM and cy osol Fusion [1,4,19] TRAK2, ALS2CR3, KIAA0549 T a icking kinesin-binding p o ein 2 (Amyo ophic la e al scle osis 2 ch omosomal egion candida e gene 3 p o ein) O ganelle a icking OMM and cy osol Fusion [1,4,19] UQCC3, C11o 83, UNQ655/PRO1286 Ubiquinol-cy och ome-c educ ase Complex assembly ac o 3 Requi ed o he assembly o he ubiquinol-cy och ome c educ ase Complex (mi ochond ial espi a o y chain Complex III o cy och ome b-c1 Complex), media ing cy och ome b ec ui men and p obably s abiliza ion wi hin he Complex IMM C is ae shape [18,69] VAT1 Synap ic esicle memb ane p o ein VAT-1 homolog (EC 1.-.-.-) (Mi o usin-binding p o ein) (P o ein MIB) Nega i ely egula es mi ochond ial usion OMM Fusion [1,19,22,70] YME1L1, FTSH1, YME1L, UNQ1868/PRO4304 ATP-dependen zinc me allop o ease YME1L1 (EC 3.4.24.-) (ATP-dependen me allop o ease F sH1) (Meg-4) (P esenilin-associa ed me allop o ease) (PAMP) (YME1-like p o ein 1) Pu a i e ATP-dependen p o ease; plays a ole in mi ochond ial o ganiza ion and mi ochond ial p o ein me abolism, including he deg ada ion o PRELID1 and OPA1 IMM C is ae shape [19,58] An ioxidan s 2018,7, 1 16 o 45 Table 3. Con . Gene Names P o ein Names NDUFS1 NADH-ubiquinone oxido educ ase 75 kDa subuni , mi ochond ial (EC 1.6.5.3) (EC 1.6.99.3) (Complex I-75kD) (CI-75kD) NDUFS3 NADH dehyd ogenase (ubiquinone) i on-sul u p o ein 3, mi ochond ial (EC 1.6.5.3) (EC 1.6.99.3) (Complex I-30kD) (CI-30kD) (NADH-ubiquinone oxido educ ase 30 kDa subuni ) NEDD8 NEDD8 (Neddylin) (Neu al p ecu so cell exp essed de elopmen ally down egula ed p o ein 8) (NEDD-8) (Ubiqui in-like p o ein Nedd8) NPM1, NPM Nucleophosmin (NPM) (Nucleola phosphop o ein B23) (Nucleola p o ein NO38) (Numa in) OAT O ni hine amino ans e ase, mi ochond ial (EC 2.6.1.13) (O ni hine del a-amino ans e ase) (O ni hine—oxo-acid amino ans e ase) (Clea ed in o: O ni hine amino ans e ase, hepa ic o m; O ni hine amino ans e ase, enal o m) OGDH 2-oxoglu a a e dehyd ogenase, mi ochond ial (EC 1.2.4.2) (2-oxoglu a a e dehyd ogenase complex componen E1) (OGDC-E1) (Alpha-ke oglu a a e dehyd ogenase) OTUB1, OTB1, OTU1, HSPC263 Ubiqui in hioes e ase OTUB1 (EC 3.4.19.12) (Deubiqui ina ing enzyme OTUB1) (OTU domain-con aining ubiqui in aldehyde-binding p o ein 1) (O ubain-1) (hOTU1) (Ubiqui in-speci ic-p ocessing p o ease OTUB1) PDIA3, ERP57, ERP60, GRP58 P o ein disul ide-isome ase A3 (EC 5.3.4.1) (58 kDa glucose- egula ed p o ein) (58 kDa mic osomal p o ein) (p58) (Disul ide isome ase ER-60) (Endoplasmic e iculum esiden p o ein 57) (ER p o ein 57) (ERp57) (Endoplasmic e iculum esiden p o ein 60) (ER p o ein 60) (ERp60) PGK1, PGKA, MIG10, OK/SW-cl.110 Phosphoglyce a e kinase 1 (EC 2.7.2.3) (Cell mig a ion-inducing gene 10 p o ein) (P ime ecogni ion p o ein 2) (PRP 2) PHB P ohibi in PHB2, BAP, REA P ohibi in-2 (B-cell ecep o -associa ed p o ein BAP37) (D-p ohibi in) (Rep esso o es ogen ecep o ac i i y) PIN1 Pep idyl-p olyl cis- ans isome ase NIMA-in e ac ing 1 (EC 5.2.1.8) (Pep idyl-p olyl cis- ans isome ase Pin1) (PPIase Pin1) (Ro amase Pin1) PPIA, CYPA Pep idyl-p olyl cis- ans isome ase A (PPIase A) (EC 5.2.1.8) (Cyclophilin A) (Cyclospo in A-binding p o ein) (Ro amase A) (Clea ed in o: Pep idyl-p olyl cis- ans isome ase A, N- e minally p ocessed) PRDX4 Pe oxi edoxin-4 (EC 1.11.1.15) (An ioxidan enzyme AOE372) (AOE37-2) (Pe oxi edoxin IV) (P x-IV) (Thio edoxin pe oxidase AO372) (Thio edoxin-dependen pe oxide educ ase A0372) PSMA3, HC8, PSC8 P o easome subuni alpha ype-3 (EC 3.4.25.1) (Mac opain subuni C8) (Mul i-ca aly ic endopep idase complex subuni C8) (P o easome componen C8) PTPN5 Ty osine-p o ein phospha ase non- ecep o ype 5 (EC 3.1.3.48) (Neu al-speci ic p o ein- y osine phospha ase) (S ia um-en iched p o ein- y osine phospha ase) (STEP) RAB14 Ras- ela ed p o ein Rab-14 RAB2A, RAB2 Ras- ela ed p o ein Rab-2A RAC1, TC25, MIG5 Ras- ela ed C3 bo ulinum oxin subs a e 1 (Cell mig a ion-inducing gene 5 p o ein) (Ras-like p o ein TC25) (p21-Rac1) RAPGEF2, KIAA0313, NRAPGEP, PDZGEF1 Rap guanine nucleo ide exchange ac o 2 (Cyclic nucleo ide as GEF) (CN asGEF) (Neu al RAP guanine nucleo ide exchange p o ein) (nRap GEP) (PDZ domain-con aining guanine nucleo ide exchange ac o 1) (PDZ-GEF1) (RA-GEF-1) (Ras/Rap1-associa ing GEF-1) RHOA, ARH12, ARHA, RHO12 T ans o ming p o ein RhoA (Rho cDNA clone 12) (h12) RNH1, PRI, RNH Ribonuclease inhibi o (Placen al ibonuclease inhibi o ) (Placen al RNase inhibi o ) (Ribonuclease/angiogenin inhibi o 1) (RAI) RPN1 Dolichyl-diphosphooligosaccha ide—p o ein glycosyl ans e ase subuni 1 (Dolichyl-diphosphooligosaccha ide—p o ein glycosyl ans e ase 67 kDa subuni ) (Ribopho in I) (RPN-I) (Ribopho in-1) RPN2 Dolichyl-diphosphooligosaccha ide—p o ein glycosyl ans e ase subuni 2 (Dolichyl-diphosphooligosaccha ide—p o ein glycosyl ans e ase 63 kDa subuni ) (RIBIIR) (Ribopho in II) (RPN-II) (Ribopho in-2) RPS15A, OK/SW-cl.82 40S ibosomal p o ein S15a (Small ibosomal subuni p o ein uS8) RPS3, OK/SW-cl.26 40S ibosomal p o ein S3 (EC 4.2.99.18) (Small ibosomal subuni p o ein uS3) S100A10, ANX2LG CAL1L CLP11 P o ein S100-A10 (Calpac in I ligh chain) (Calpac in-1 ligh chain) (Cellula ligand o annexin II) (S100 calcium-binding p o ein A10) (p10 p o ein) (p11) An ioxidan s 2018,7, 1 17 o 45 Table 3. Con . Gene Names P o ein Names SAMM50, SAM50 CGI-51 TRG3 So ing and assembly machine y componen 50 homolog (T ans o ma ion- ela ed gene 3 p o ein) (TRG-3) SELENBP1, SBP Selenium-binding p o ein 1 (56 kDa selenium-binding p o ein) (SBP56) (SP56) SFXN1 Side o lexin-1 (T ica boxyla e ca ie p o ein) (TCC) SH3GLB2, KIAA1848, PP578 Endophilin-B2 (SH3 domain-con aining GRB2-like p o ein B2) SIRT2, SIR2L, SIR2L2 NAD-dependen p o ein deace ylase si uin-2 (EC 3.5.1.-) (Regula o y p o ein SIR2 homolog 2) (SIR2-like p o ein 2) SLC25A13, ARALAR2 Calcium-binding mi ochond ial ca ie p o ein A ala 2 (Ci in) (Mi ochond ial aspa a e glu ama e ca ie 2) (Solu e ca ie amily 25 membe 13) SLC25A18, GC2 Mi ochond ial glu ama e ca ie 2 (GC-2) (Glu ama e/H(+) sympo e 2) (Solu e ca ie amily 25 membe 18) SLC25A5, ANT2 ADP/ATP anslocase 2 (ADP, ATP ca ie p o ein 2) (ADP, ATP ca ie p o ein, ib oblas iso o m) (Adenine nucleo ide ansloca o 2) (ANT 2) (Solu e ca ie amily 25 membe 5) (Clea ed in o: ADP/ATP anslocase 2, N- e minally p ocessed) SLC9A3R1, NHERF, NHERF1 Na(+)/H(+) exchange egula o y co ac o NHE-RF1 (NHERF-1) (Ez in- adixin-moesin-binding phosphop o ein 50) (EBP50) (Regula o y co ac o o Na(+)/H(+) exchange ) (Sodium-hyd ogen exchange egula o y ac o 1) (Solu e ca ie amily 9 iso o m A3 egula o y ac o 1) SSBP1, SSBP Single-s anded DNA-binding p o ein, mi ochond ial (M -SSB) (M SSB) (PWP1-in e ac ing p o ein 17) TPD52 Tumo p o ein D52 (P o ein N8) TPM1, C15o 13, TMSA T opomyosin alpha-1 chain (Alpha- opomyosin) (T opomyosin-1) TPM2, TMSB T opomyosin be a chain (Be a- opomyosin) (T opomyosin-2) TPM3 T opomyosin alpha-3 chain (Gamma- opomyosin) (T opomyosin-3) (T opomyosin-5) (hTM5) TPM4 T opomyosin alpha-4 chain (TM30p1) (T opomyosin-4) TUBA1A, TUBA3 Tubulin alpha-1A chain (Alpha- ubulin 3) (Tubulin B-alpha-1) (Tubulin alpha-3 chain) (Clea ed in o: De y osina ed ubulin alpha-1A chain) TUBB, TUBB5, OK/SW-cl.56 Tubulin be a chain (Tubulin be a-5 chain) TUBB4B, TUBB2C Tubulin be a-4B chain (Tubulin be a-2 chain) (Tubulin be a-2C chain) TUFM Elonga ion ac o Tu, mi ochond ial (EF-Tu) (P43) UQCRB, UQBP Cy och ome b-c1 complex subuni 7 (Complex III subuni 7) (Complex III subuni VII) (QP-C) (Ubiquinol-cy och ome c educ ase complex 14 kDa p o ein) UQCRFS1 Cy och ome b-c1 complex subuni Rieske, mi ochond ial (EC 1.10.2.2) (Complex III subuni 5) (Cy och ome b-c1 complex subuni 5) (Rieske i on-sul u p o ein) (RISP) (Ubiquinol-cy och ome c educ ase i on-sul u subuni ) (Clea ed in o: Cy och ome b-c1 complex subuni 11 (Complex III subuni IX) (Ubiquinol-cy och ome c educ ase 8 kDa p o ein)) UQCRFS1P1, UQCRFSL1 Pu a i e cy och ome b-c1 complex subuni Rieske-like p o ein 1 (Ubiquinol-cy och ome c educ ase Rieske i on-sul u subuni pseudogene 1) UQCRH Cy och ome b-c1 complex subuni 6, mi ochond ial (Complex III subuni 6) (Complex III subuni VIII) (Cy och ome c1 non-heme 11 kDa p o ein) (Mi ochond ial hinge p o ein) (Ubiquinol-cy och ome c educ ase complex 11 kDa p o ein) USMG5, DAPIT, HCVFTP2, PD04912 Up egula ed du ing skele al muscle g ow h p o ein 5 (Diabe es-associa ed p o ein in insulin-sensi i e issues) (HCV F- ansac i a ed p o ein 2) VCP T ansi ional endoplasmic e iculum ATPase (TER ATPase) (EC 3.6.4.6) (15S Mg(2+)-ATPase p97 subuni ) (Valosin-con aining p o ein) (VCP) VDAC1, VDAC Vol age-dependen anion-selec i e channel p o ein 1 (VDAC-1) (hVDAC1) (Ou e mi ochond ial memb ane p o ein po in 1) (Plasmalemmal po in) (Po in 31HL) (Po in 31HM) VDAC2 Vol age-dependen anion-selec i e channel p o ein 2 (VDAC-2) (hVDAC2) (Ou e mi ochond ial memb ane p o ein po in 2) VDAC3 Vol age-dependen anion-selec i e channel p o ein 3 (VDAC-3) (hVDAC3) (Ou e mi ochond ial memb ane p o ein po in 3) VIM Vimen in YWHAE 14-3-3 p o ein epsilon (14-3-3E) YWHAZ 14-3-3 p o ein ze a/del a (Fac o ac i a ing exoenzyme S) (FAS) (P o ein kinase C inhibi o p o ein 1) (KCIP-1) An ioxidan s 2018,7, 1 18 o 45 An ioxidan s 2018, 7, 1 16 o 48 ubiquinol cy och ome c educ ase i on–sulphu subuni , and he cy och ome b-c1 Complex subuni 6) and Complex IV ( he cy och ome c oxidase subuni 4, he cy och ome c oxidase subuni 5A, he cy och ome c oxidase subuni 6C, he cy och ome c oxidase subuni 7C, and he cy och ome c oxidase polypep ide I). Pi o al o he p ope a chi ec u e o he mi ochond ial c is ae is he p o ein OPA1 [3]. Al e a ions we e ound o occu in he exp ession o he calcium-binding mi ochond ial ca ie p o ein A ala 2 (Slc25A), which ac s in conjunc ion wi h OPA1 o sense modi ica ions o he subs a e le els o ene gy p oduc ion. Following his in e ac ion, he c is ae a e na owed and he dime iza ion o he ATP syn hase is s imula ed [18]. The mi ochond ial c is ae s uc u e is no solely main ained by p o eins, bu also by ca diolipin lipids [18], and se e al ca diolipin binding p o eins ha e been desc ibed o be p esen a he mi ochond ial memb ane, amongs hem he P ohibi in p o ein amily. P ohibi in and P ohibi in-2 appea ed o be al e ed in he con ex o Pa kinson’s disease in ou analysis (Table 2). These p o eins a e known o be o ganized in complexes wi hin he inne mi ochond ial memb ane and a e impo an o he p ope o ganiza ion o he c is ae mo phology and mi ochond ial espi a ion [53,92]. Mo eo e , hese p o eins a e in ol ed in he u no e o he subuni s o he mi ochond ial espi a o y chain and pa icipa e in he assembly o he Complex IV om he espi a o y chain [93,94]. The e is e idence ha abe an c is ae mo phology a ec s he p ope assembly o he OXPHOS complexes, bu also ha he lack o ATP syn hase subuni s impac s he mo phology o he c is ae [95,96]. The la e has been suppo ed by s udies showing ha ATP syn hase dime iza ion o ces memb ane cu a u e [97]. In e es ingly, mi ochond ial mo phology also elies on he cellula ene ge ic s a e since, by comp omising mi ochond ial memb ane po en ial, mi ochond ial agmen a ion is induced [98]. In addi ion, dime o ma ion o he F1F0-ATP syn hase a ec s mi ochond ial c is ae s uc u e [95]. 3.2. Binding Pa ne s o Mi ochond ial P o eins Di e en ially Exp essed in Pa kinson’s Disease Mi ochond ia a e o ganelles wi h impo an oles in many cellula p ocesses, hence we nex explo ed he binding pa ne s desc ibed o he mi ochond ial p o eins di e en ially exp essed in Pa kinson’s disease (Table 2). Using he HIPPIE ool [72,99–101], we de e mined he comple e lis o binding pa ne s, which is depic ed in Supplemen a y Table S2 (Figu e 1). This so wa e p o ides in o ma ion on human p o ein-p o ein in e ac ions wi h high con idence sco es ha a e due o he amoun o suppo ing da a a ailable as well as de i ed om anno a ed in o ma ion [72,99]. In o al, o he 22 mi ochond ial-shaping p o eins al e ed in Pa kinson’s disease, we ound 1683 hin s o in e ac ing p o eins. Since some o he mi ochond ial-shaping p o eins ha e in e ac ing p o eins in common, hese hin s co espond o 1008 di e en p o eins. When we c oss- e e enced hese binding pa ne s wi h he lis o p o eins ound o be modi ied in he con ex o Pa kinson’s disease (Supplemen a y Table S1), 108 common hin s we e iden i ied (Figu e 3, Table 3, and Supplemen a y Table S3). In Supplemen a y Table S3, he di e en hin s o he p o eins lis ed in Table 3 wi hin he di e en p o eomics-based s udies used in he p esen wo k a e desc ibed. Figu e 3. Venn diag am displaying he compa ison o he numbe o he binding pa ne s o he mi ochond ial-shaping p o eins a ec ed in Pa kinson’s disease (Table 2) and he p o eins ound o be di e en ially exp essed in he con ex o Pa kinson’s disease (Supplemen a y Table S1). The Venn diag am was cons uc ed using he Venny 2.1 so wa e [71]. PD—Pa kinson’s disease. Figu e 3. Venn diag am displaying he compa ison o he numbe o he binding pa ne s o he mi ochond ial-shaping p o eins a ec ed in Pa kinson’s disease (Table 2) and he p o eins ound o be di e en ially exp essed in he con ex o Pa kinson’s disease (Supplemen a y Table S1). The Venn diag am was cons uc ed using he Venny 2.1 so wa e [71]. PD—Pa kinson’s disease. The p o eins used o sea ch o he binding pa ne s we e mi ochond ial p o eins, hus al e a ions in he mi ochond ial cellula componen s we e expec ed. In his ega d, he down egula ion o he inne mi ochond ial memb ane and he mi ochond ial p o on- anspo ing ATP syn hase complex was an icipa ed. Se e al o he p o eins ound o be al e ed in he con ex o Pa kinson’s disease (Table 2) a e p o eins loca ed a he inne mi ochond ial memb ane, and he al e a ion o hese componen s has also p e iously been desc ibed in he pa hology [7]. In e es ingly, i has been shown ha he ubiqui in-p o easome sys em egula es he le el o p o eins a ge ed o he mi ochond ial in e memb ane space, and his p ocess depends on he mi ochond ial in e memb ane space impo machine y [ 102 ]. Addi ionally, i has been shown ha he ubiqui in-p o easome sys em ac s on he egula ion o he mi ochond ial biogenesis [ 103 ]. In his s udy, we ound an up egula ion o he p o easome, which co obo a es he e idence o i s dys unc ion in Pa kinson’s disease [ 103 , 104 ]. ROS le els a e inc eased in Pa kinson’s disease and a e esponsible o he oxida i e modi ica ion o lipids, DNA, and p o eins [ 105 ]. These modi ica ions migh lead o mis olded p o eins and agg ega ion [ 106 ]. Mi ochond ial p o eins migh be dys unc ional due o he ha m ul e ec s o ROS, which no only migh modi y he olded p o eins, bu also a ec he inco po a ion o newly syn he ized mi ochond ial p o eins since hey a e ansla ed in he cy osol and mus be anspo ed un olded in o he mi ochond ia [ 103 ]. In an oxida i e s ess scena io, as in Pa kinson’s disease, he isk o he al e a ion o un olded p o eins and consequen emo al by he p o easome is highe , educing he amoun o mi ochond ial p o eins a ailable. Besides, i is known ha ou e mi ochond ial memb ane p o eins in ol ed in mi ochond ial usion a e egula ed by ubiqui ina ion and ha his p ocess is induced by s ess [19]. Mi ochond ial dynamics no only elies on mi ochond ial usion and ission p o eins, bu also on he con ac si es be ween mi ochond ia and he ER, which a e undamen al o he ini ial ission p ocess [ 107 ]. I has been desc ibed ha he shape- o ming p o eins con ol mi ochond ial mo phology by media ing he a achmen o he mi ochond ia o he cy oskele on and he ER [ 107 , 108 ], and hey can also connec he inne and ou e mi ochond ial memb anes, hence in luencing he impo and assembly o mi ochond ial p o eins [ 109 ]. Rega ding he up egula ion o he melanosome as a cellula componen , al hough i is an o ganelle no p esen in neu onal cells, when we look closely a he p o eins con ibu ing o his node, we ind ha h ee o he p o eins a e hea shock p o eins. These p o eins a e key componen s in ensu ing p ope p o ein unc ion and a e exp essed in esponse o s ess, con olling he subsequen deg ada ion o mis olded p o eins, which is also in line wi h he up egula ion o he p o easome complex and he occu ence o he oxida i e s ess cha ac e is ic o he diso de . The mi ochond ial cy och ome bc1 complex om he espi a o y chain (Complex III) is one o he main p oduce s o ROS, oge he wi h he Complex I [ 110 ]. Al hough Complex I elease supe oxide in o he mi ochond ial ma ix, Complex III does i in o he in e memb ane space and he cy osol [ 111 ]. In he pa hobiology o Pa kinson’s disease, i is well accep ed ha he e is an inc ease in ROS leading An ioxidan s 2018,7, 1 19 o 45 o oxida i e s ess [ 105 ], which is in ag eemen wi h he up egula ion o he cellula mi ochond ia componen o he espi a o y chain Complex III ound in ou analysis. This complex is localized in he inne mi ochond ial memb ane, a he c is ae, and has h ee ansmemb ane subuni s in which he p os he ic g oups in ol ed in he edox eac ions a e loca ed. They mus be dime ized o p ope unc ioning, which is also dependen on he mi ochond ial memb ane po en ial [ 110 ], sugges ing ha al e a ions in he o ganiza ion o he inne mi ochond ial memb ane migh a ec hei unc ion. An ioxidan s 2018, 7, 1 22 o 48 bu also a ec he inco po a ion o newly syn he ized mi ochond ial p o eins since hey a e ansla ed in he cy osol and mus be anspo ed un olded in o he mi ochond ia [103]. In an oxida i e s ess scena io, as in Pa kinson’s disease, he isk o he al e a ion o un olded p o eins and consequen emo al by he p o easome is highe , educing he amoun o mi ochond ial p o eins a ailable. Besides, i is known ha ou e mi ochond ial memb ane p o eins in ol ed in mi ochond ial usion a e egula ed by ubiqui ina ion and ha his p ocess is induced by s ess [19]. Figu e 4. Cy oscape ne wo k o he main cellula componen s associa ed wi h mi ochond ial-shaping p o eins in he con ex o Pa kinson’s disease. The binding pa ne s o he mi ochond ial-shaping p o eins ound o be modi ied in di e en p o eomics-based app oaches in he con ex o Pa kinson’s disease acco ding o he Human In eg a ed P o ein-P o ein In e ac ion E e ence (HIPPIE) and appea ing as modi ied in p o eomics-based s udies on Pa kinson’s disease we e subjec ed o ne wo k analysis using he plugin ClueGo om he so wa e Cy oscape o analyze he cellula componen s ep esen ed by he p o eins om he lis . G ay scale nodes co espond o cellula componen s ha we e ound o be equally up- and down egula ed in di e en s udies, while g een and ed nodes a e ep esen a i e o up egula ed and down egula ed cellula componen s espec i ely, in he con ex o Pa kinson’s disease. The inc ease in g een and ed colo g adien ep esen s highe amoun s o he con ibu ion o up- and down egula ed p o eins, espec i ely. The size o he nodes is indica i e o hei s a is ical signi icance. Figu e 4. Cy oscape ne wo k o he main cellula componen s associa ed wi h mi ochond ial-shaping p o eins in he con ex o Pa kinson’s disease. The binding pa ne s o he mi ochond ial-shaping p o eins ound o be modi ied in di e en p o eomics-based app oaches in he con ex o Pa kinson’s disease acco ding o he Human In eg a ed P o ein-P o ein In e ac ion E e ence (HIPPIE) and appea ing as modi ied in p o eomics-based s udies on Pa kinson’s disease we e subjec ed o ne wo k analysis using he plugin ClueGo om he so wa e Cy oscape o analyze he cellula componen s ep esen ed by he p o eins om he lis . G ay scale nodes co espond o cellula componen s ha we e ound o be equally up- and down egula ed in di e en s udies, while g een and ed nodes a e ep esen a i e o up egula ed and down egula ed cellula componen s espec i ely, in he con ex o Pa kinson’s disease. The inc ease in g een and ed colo g adien ep esen s highe amoun s o he con ibu ion o up- and down egula ed p o eins, espec i ely. The size o he nodes is indica i e o hei s a is ical signi icance. An ioxidan s 2018,7, 1 20 o 45 A close look a he ne wo k shows ha “muscle hin ilamen opomyosin” is connec ed o cellula componen s ela ed o he ac in cy oskele on (“ac in ilamen ”, “s ess ibe ”, and “ ilamen ous ac in”). As desc ibed abo e, he cy oskele on also plays a ole in he dynamics and mo emen o he mi ochond ia [ 108 ]. In e es ingly, in he con ex o Pa kinson’s disease some models (bo h gene ic and d ug-based) showed a nega i e impac on he dynamics o he ac in cy oskele on and he o ma ion o s ess ibe s [108,112,113]. 3.3. Biological P ocesses Associa ed wi h Mi ochond ial-Shaping P o eins A ec ed in Pa kinson’s Disease To ob ain in o ma ion on he biological p ocesses ela ed o he mi ochond ial-shaping p o eins a ec ed in Pa kinson’s disease, we unde ook a bioin o ma ic app oach using he plugin ClueGo om he Cys oscope so wa e (Figu e 5and Table 4). This plugin allows he ex ac ion o he biological meaning o la ge lis s o p o eins [ 114 ]. O e all, a ound 44% al e ed p ocesses a e ela ed o ene gy p oduc ion by he mi ochond ia. This con ibu ion was expec ed since he dys unc ion o his o ganelle is a hallma k o he disease. An ioxidan s 2018, 7, 1 24 o 48 Figu e 5. Cy oscape ne wo k o he main biological p ocesses associa ed wi h mi ochond ial-shaping p o eins in he con ex o Pa kinson’s disease. The binding pa ne s o he mi ochond ial-shaping p o eins ound modi ied in di e en p o eomics-based app oaches in he con ex o Pa kinson’s disease we e subjec ed o ne wo k analysis using he plugin ClueGo om he so wa e Cy oscape o analyze he biological p ocesses a ec ed in he disease. G ay scale nodes co espond o biological pa hways ha we e ound o be equally up- and down egula ed in di e en s udies, while g een and ed nodes a e ep esen a i e o up egula ed and down egula ed biological pa hways, espec i ely, in he con ex o Pa kinson’s disease. The inc ease in g een and ed colo g adien ep esen s highe amoun s o he con ibu ion o up- and down egula ed p o eins, espec i ely. The size o he nodes is indica i e o hei s a is ical signi icance. Table 4. Lis o biological p ocesses ela ed o he mi ochond ial-shaping p o eins a ec ed in Pa kinson’s disease. Up egula ed Down egula ed ATP biosyn he ic p ocess ATP me abolic p ocess Posi i e egula ion o ni ic oxide biosyn he ic p ocess Memb ane a assembly Response o un olded p o ein Posi i e egula ion o s ess ibe assembly Audi o y ecep o cell mo phogenesis Glu ha ione de i a i e biosyn he ic p ocess Binding o spe m o zona pellucida P o ein N-linked glycosyla ion ia aspa agine Regula ion o p o ein dephospho yla ion Glucoco icoid ecep o signaling pa hway Mi ochond ial elec on anspo ubiquinol o cy och ome c ER-nucleus signaling pa hway Regula ion o exi om mi osis Subs an ia nig a de elopmen NAD me abolic p ocess Posi i e egula ion o NFkB signaling Muscle ilamen sliding Mi ochond ial ansmemb ane anspo Regula ion o complemen ac i a ion Mi ochond ial elec on anspo cy och ome c o oxygen Midb ain de elopmen and posi i e egula ion o Respi a o y elec on anspo chain Figu e 5. Cy oscape ne wo k o he main biological p ocesses associa ed wi h mi ochond ial-shaping p o eins in he con ex o Pa kinson’s disease. The binding pa ne s o he mi ochond ial-shaping p o eins ound modi ied in di e en p o eomics-based app oaches in he con ex o Pa kinson’s disease we e subjec ed o ne wo k analysis using he plugin ClueGo om he so wa e Cy oscape o analyze he biological p ocesses a ec ed in he disease. G ay scale nodes co espond o biological pa hways ha we e ound o be equally up- and down egula ed in di e en s udies, while g een and ed nodes a e ep esen a i e o up egula ed and down egula ed biological pa hways, espec i ely, in he con ex o Pa kinson’s disease. The inc ease in g een and ed colo g adien ep esen s highe amoun s o he con ibu ion o up- and down egula ed p o eins, espec i ely. The size o he nodes is indica i e o hei s a is ical signi icance. An ioxidan s 2018,7, 1 21 o 45 Table 4. Lis o biological p ocesses ela ed o he mi ochond ial-shaping p o eins a ec ed in Pa kinson’s disease. Up egula ed Down egula ed ATP biosyn he ic p ocess ATP me abolic p ocess Posi i e egula ion o ni ic oxide biosyn he ic p ocess Memb ane a assembly Response o un olded p o ein Posi i e egula ion o s ess ibe assembly Audi o y ecep o cell mo phogenesis Glu ha ione de i a i e biosyn he ic p ocess Binding o spe m o zona pellucida P o ein N-linked glycosyla ion ia aspa agine Regula ion o p o ein dephospho yla ion Glucoco icoid ecep o signaling pa hway Mi ochond ial elec on anspo ubiquinol o cy och ome c ER-nucleus signaling pa hway Regula ion o exi om mi osis Subs an ia nig a de elopmen NAD me abolic p ocess Posi i e egula ion o NFkB signaling Muscle ilamen sliding Mi ochond ial ansmemb ane anspo Regula ion o complemen ac i a ion Mi ochond ial elec on anspo cy och ome c o oxygen Midb ain de elopmen and posi i e egula ion o neu ophil chemo axis Respi a o y elec on anspo chain Oxida i e phospho yla ion Mi ochond ial espi a o y chain Complex I assembly Mi ochond ial elec on anspo NADH o ubiquinone Mi ochond ia espi a o y chain complex assembly Mi ochond ial ATP syn hesis coupled o elec on anspo Cellula espi a ion and p o on anspo In e es ingly, o he biological p ocesses a e ela ed o he occu ence o oxida i e s ess and he espec i e al e a ions in p o eins, which is also a known cha ac e is ic o Pa kinson’s disease [ 105 ]. In his ega d, he posi i e egula ion o he ni ic oxide (NO) biosyn he ic p ocess ha e been shown o occu in his diso de , which is ele an o neu onal dea h. When NO syn hases a e abla ed, animals a e p o ec ed agains he e ec o he MPTP oxin [ 115 ]. I is also known ha NO no only induces oxida i e s ess bu also neu onal dea h [ 116 , 117 ]. The down egula ion o he glu a hione de i a i e biosyn he ic p ocess is also a cha ac e is ic o an oxida i e s ess scena io, which has also been desc ibed in Pa kinson’s disease [ 118 ]. This pep ide ac s as a cellula an ioxidan , which is p oduced by neu ons and glial cells, and i has been p oposed as an impo an molecule o he apeu ic pu poses in he con ex o Pa kinson’s disease [ 118 , 119 ]. Mo eo e , he up egula ion o he esponse o un olded p o eins is impo an in an oxida i e s ess scena io whe e p o eins and pep ides can be oxida i ely modi ied wi h a ha m ul e ec on hei h ee-dimensional (3D) s uc u e, wi h agg ega ion ha ing a nega i e impac on hei unc ion [ 106 ]. Besides, p o ein oxida i e modi ica ions and agg ega ion ha e been also ela ed o he dec eased in glu a hione le els [120]. As s a ed along his wo k, he cellula cy oskele on is one o he mechanisms con ibu ing o he de ini ion o mi ochond ial mo phology [ 108 ]. In ac , modi ica ion o he ac in cy oskele on has been p obed in Pa kinson’s disease [ 108 , 112 , 113 ]. Mi ochond ial usion and ission p ocesses a e a ec ed by he in e ac ion o he mi ochond ia wi h he cy oskele on. I has been desc ibed ha he usion p ocess can be delayed when ac in ilamen s a e depolyme ized [ 121 ]. The ac in cy oskele on is also in ol ed in he ission p ocess [ 38 ]. In ou ne wo k, se e al p ocesses a e ela ed o he ac in cy oskele on, such as he up egula ion o he p ocess o “muscle ilamen sliding” and he down egula ion o he “posi i e egula ion o s ess ibe assembly”. In e es ingly, a e a close look a he modi ied biological p ocess o “binding o spe m o zona pellucida”, we obse ed ha he p o eins connec ed o his p ocess a e molecula chape ones and, ema kably, TCP-1-epsilon is known o play a ole in he olding o ac in and ubulin [122]. Rega ding he “audi o y ecep o cell mo phogenesis” biological p ocesses, i is impo an o no e ha he p o ein Rac1 con ibu es o his pa hway and is in ol ed in he egula ion o sec e o y p ocesses, he phagocy osis o dea h cells, cell pola iza ion, and he o ma ion o memb ane u les. In he con ex o Pa kinson’s disease, i has been shown o con ibu e o a ROS gene a ing pa hway An ioxidan s 2018,7, 1 22 o 45 ac ing wi h Nox1, causing neu onal dea h [ 123 ]. In e es ingly, he o he componen o his node is he NHERF-1 p o ein, which has been shown o ac as a sca old o connec ing plasma memb ane p o eins wi h membe s o he ERM (ez in/moesin/ adixin) amily, aiding in hei link o he ac in cy oskele on o he egula ion o hei su ace exp ession [124]. Wi hin he highligh ed p ocess o “ egula ion o p o ein dephospho yla ion” in ol ed in he egula ion o p o ein unc ion, we ound an in e es ing p o ein con ibu ion o his pa hway: he Pep idyl-p olyl cis- ans isome ase (Pin1). This p o ein has been shown o be in ol ed in he disease, being up egula ed in cellula and animal models as well as in SN in pa ien s [ 125 ]. The al e a ion o his biological p ocess migh ha e an impac on s ess esponses, immune unc ion, and neu onal su i al [ 126 ]. Also, his pa hway is undamen al o p ope mi ochond ial unc ioning and signaling since, in esponse o he me abolic s a e o he cell, mi ochond ial p o eins om he impo machine y migh be egula ed by phospho yla ion [127]. In he “ egula ion o exi om mi osis” p ocess, wo in e es ing p o eins eme ge: P ohibi in-2 and he NAD-dependen p o ein deace ylase si uin-2. The la e deace yla es lysines on his ones, alpha- ubulin, and o he p o eins [ 128 ]. By ac ing on ubulin i has a di ec impac on mic o ubule unc ion. Tubulin can be subjec ed o di e en pos - ansla ional modi ica ions wi h in luence on he mic o ubule polyme iza ion s a e and i s unc ion, such as ace yla ion [ 129 ]. This modi ica ion on he esidue K40 has been epo ed o al e he in e ac ion o p o eins wi h he cy oskele on, wi h subsequen impac on he in acellula anspo along he mic o ubules [ 129 ]. As desc ibed in his wo k, his may a ec mi ochond ia mo phology and dynamics. Pa kinson’s disease has long been linked o inc eased in lamma o y esponse [ 130 ]. In ou analysis we ound ha he p ocesses ela ed o he in lamma o y esponse we e up egula ed: “posi i e egula ion o neu ophil chemo axis” and “ egula ion o complemen ac i a ion”. In e es ingly, om he las p ocess, wo o he implica ed p o eins belong o he P ohibi in amily, which ha e been desc ibed o be in ol ed in he egula ion o mi ochond ial espi a ion [ 131 ]. Rega ding he down egula ion o he p ocess o he “glucoco icoid ecep o signaling pa hway” i is impo an o no e ha a dec ease in he le els o he glucoco icoid ecep o in bo h he SN o pa ien s and in animal models o he disease has been epo ed [ 132 , 133 ]. These ecep o s egula e in lamma ion and a e dys egula ed in mic oglia in he con ex o Pa kinson’s disease. Dys egula ion has been p oposed o sus ain he ch onic in lamma o y s a e obse ed in his diso de as well as he inc eased pe meabili y o he blood b ain ba ie , which migh inc ease neu onal ulne abili y [ 132 , 133 ]. Ano he pa hway ela ed o he in lamma o y p ocess is down egula ed: “posi i e egula ion o NF-kB signaling”, in which he p o ein ibosomal p o ein S3 s ands ou . In e es ingly, his p o ein has been p oposed o p o ec he dopamine gic neu ons om apop osis [134]. Wi hin he ne wo k, he biological p ocesses o “midb ain de elopmen ” and “subs an ia nig a de elopmen ” sha e h ee p o eins: Ac in, Complex I 30 kD om he mi ochond ial espi a o y chain, and he 14-3-3 p o ein epsilon. As desc ibed p e iously, he dys unc ion o Complex I om he mi ochond ial espi a o y chain was he i s indica ion o he mi ochond ia in ol emen in he pa hobiology o Pa kinson’s disease [ 7 , 8 ]. The con ibu ion o he cy oskele on has also been shown, in which ac in has a key ole in he sec e ion o he synap ic esicles con en ha migh be hen ansla ed in o a dec ease in he con en o neu o ansmi e s in he synap ic cle [ 135 ]. Al hough he 14-3-3 p o ein is ubiqui ously exp essed and pa icipa es in he egula ion o many signaling pa hways, i has also been ound o be a cons i uen o he Lewy bodies o Pa kinson’s disease pa ien s [136]. In Pa kinson’s disease he e is a c i ical modi ica ion in he lipid a s composi ion, and inc easing e idence shows hei con ibu ion o he diso de [ 137 – 139 ]. Lipid a s ha e a ole in di e se cellula p ocesses such as memb ane a icking, signal ansduc ion, and cy oskele al o ganiza ion. Thei al e a ion can also ha e a nega i e impac on p o ein-p o ein in e ac ions, which a e undamen al p ocesses o he o ma ion o p o ein supe complexes [ 138 ]. In e es ingly, we ound he p ocess o “memb ane a assembly” o be down egula ed. No only was he p o ein Flo illin-1, a well-known componen o he lipid a s, ound o con ibu e o his node, bu also he p o ein An ioxidan s 2018,7, 1 23 o 45 S100A10. The S100 amily o p o eins a e in ol ed in se e al cellula p ocesses such as he egula ion o cell p oli e a ion and di e en ia ion, apop osis, calcium homeos asis, ene gy me abolism, and in lamma ion. In e es ingly, hey also in e ac wi h cy oskele al and o he cellula p o eins [ 140 ]. Some o he memb ane p o eins ha in e ac wi h he S100A10 a e: Annexin 2, ion channels, ac in binding p o eins, and he se o onin ecep o [ 140 ]. This p o ein has been p oposed o unc ion on memb ane epai and was shown o be down egula ed in dep essi e-like s a es in mice, wi h i s exp ession being egula ed by neu o ophins [141,142]. N-glycosyla ion is a pos - ansla ional modi ica ion ha is ound in memb ane p o eins and sec e ed p o eins; amongs hem a e g ow h ac o s and hei ecep o s [ 143 ]. In ou analysis, we ound ha he p ocess o “p o ein N-linked glycosyla ion ia aspa agine” was down egula ed. This modi ica ion akes places in he ER and in he Golgi, ha ing an e ec on p o ein unc ion. E idence show ha N-glycosyla ion is impo an o p ope neu onal unc ion and has a ole in synap ic ansmission [144], hence ha ing a p o ound impac on he disease [145]. The occu ence o a ole o he ER s ess in he con ex o Pa kinson’s disease [ 146 ] is suppo ed h ough new e idence, and he p ocess o he “ER-nucleus signaling pa hway” was ound o be down egula ed in ou analysis. In his node, we ound he LMNA. Lamins a e ilamen ous p o eins ha con ibu e o he nucleus a chi ec u e and gene exp ession [ 147 , 148 ]. These p o eins also in e ac wi h he ac in cy oskele on, which is known o be a ec ed in Pa kinson’s disease [ 108 , 112 , 113 , 149 ]. The o he p o eins (cal e iculin and he hea shock 70 kDa p o ein 5) a e chape ones in ol ed in p o ein olding and he o ma ion o mul ime ic complexes [ 150 , 151 ], playing a c ucial ole in an oxida i e s ess scena io. Addi ionally, in he case o ission, no only ac in bu also he ER is in ol ed in he p ocess o mi ochond ial p econs uc ion and DRP1 assembly [107]. 4. Discussion Mi ochond ia a e undamen al o ganelles o cells, wo king mainly on ene gy p oduc ion, calcium homeos asis, and apop osis. De ec s in he mi ochond ial espi a o y chain ha e ecei ed much o he a en ion as a key playe in he pa hobiology o Pa kinson’s disease [ 8 , 152 ]. Howe e , addi ional modi ica ions o he mi ochond ia a e being inc easingly epo ed [ 153 , 154 ]. Besides, i is now known ha he inhibi ion o Complex I om he mi ochond ial espi a o y chain by MPP+ and o enone does no di ec ly igge cy och ome c elease bu , ins ead, inc eases he amoun o cy och ome c wi hin he mi ochond ial in e memb ane space [ 155 ], indica ing ha he e a e o he p ocesses equi ed o igge neu onal dea h. Amongs hem a e changes in mi ochond ial dynamics (i.e., al e a ions in he usion and ission p ocesses, al e a ion o c is ae mo phology) [85,156]. Inc easing e idence shows ha o p ope mi ochond ial unc ion, p ocesses like mi ochond ial usion, ission, and u no e a e undamen al, and hei dys unc ion has been linked o di e en diseases [ 1 , 3 ]. In he con ex o Pa kinson’s disease, an inc ease in mi ochond ial ission has been epo ed [ 73 , 157 , 158 ], sugges ing ha his excessi e agmen a ion migh hen enhance cy och ome c elease om mi ochond ia and subsequen ly igge ing apop osis [ 159 ]. Howe e , we ound he p ocess o c is ae emodeling o be mo e highligh ed in ou analysis ega ding he al e a ion o he mi ochond ial-shaping p o eins in Pa kinson’s disease. No ably, he al e a ion o he mi ochond ia c is ae and memb ane migh a ec he p ope binding o cy och ome c, a o ing i s elease o he cy osol and ini ia ing he apop o ic p ocess [ 155 ]. Some e idence o mi ochond ial c is ae emodeling exis s in he con ex o Pa kinson’s disease. One s udy using a cyb id cell line cons uc ed wi h mi ochond ia DNA isola ed om cells om Pa kinson’s disease pa ien s showed ha he e we e de iciencies in bo h complexes o he mi ochond ial espi a o y chain I and IV, and cells con ained a non-homogenous mi ochond ial popula ion wi h di e en mo phologies anging om enla ged o swollen and ounded in shape, which also displayed di e en mi ochond ial memb ane po en ial alues [ 160 ]. A he ul as uc u al le el, some mi ochond ia om his cyb id displayed a dec eased in he ma ix densi y and con ained a educed numbe o c is ae and a discon inuous ou e mi ochond ial memb ane [160]. Simila ly, in a s udy using ansgenic mice o mu a ed α-synuclein, mo phological An ioxidan s 2018,7, 1 24 o 45 al e a ions on he c is ae we e also obse ed, showing a diso de ed inne memb ane and swollen ma ix [ 34 ]. Howe e , his ype o s udy wi h samples om human pa ien s is insu icien , and an inc easing numbe o s udies aiming a deciphe ing he ul as uc u e o he mi ochond ia in Pa kinson’s disease by elec on and supe - esolu ion mic oscopy a e equi ed. I is known ha c is ae emodeling is undamen al du ing apop osis o he p ope elease o cy och ome c [ 27 ], and ha he c is ae a e he si es we e he OXPHOS componen s a e loca ed (94% o Complex II and ATP syn hase [ 161 ], and 85% o cy och ome c [ 27 ]). Compelling da a indica e ha he shape o he c is ae is c ucial o he modula ion o he OXPHOS unc ion [ 18 ], and elies on he cellula s a e [ 162 , 163 ]. Dis up ion o he c is ae junc ions is a esul o he elease o apop o ic ac o s om he mi ochond ia [ 27 ]. Rema kably, in ou analysis mos o he p o eins in ol ed in mi ochond ial dynamics ha we e ound o be al e ed in he con ex o Pa kinson’s disease ha e been p e iously epo ed o play a ole in he mo phology o he c is ae. When imaging mi ochond ia, ou main componen s can be dis inguished a he ul as uc u e le el: he ou e mi ochond ial memb ane (OMM), impo an o egula ing memb ane pe meabili y and he impo /expo o mi ochond ial p o eins; he inne mi ochond ial memb ane (IMM), whe e he mi ochond ial espi a o y chain is placed ( he in agina ions o he IMM in o he ma ix a e he so-called mi ochond ia c is ae); he in e memb ane space (IMS), which is he space be ween he wo mi ochond ial memb anes; and he ma ix, whe e he componen s o he ica boxylic acid (TCA) cycle a e loca ed. The inne mi ochond ial memb ane is o ganized in o h ee specialized zones: he inne bounda y memb ane, whe e he inne and ou e memb anes a e associa ed, con aining p o eins o he p o ein impo machine y; he c is ae, which a e he inne memb ane in agina ions ha a e en iched in p o eins in ol ed in p o ein ansloca ion and syn hesis as well as p o eins in ol ed in i on-sul u biogenesis; and he c is ae junc ions, which a e he po ion o he c is ae ha a e cons ic ed and whe e he MICOS Complex is loca ed [3]. Fundamen al o cell su i al is he implica ion o he mi ochond ia in he egula ion o apop osis. Wi hin his o ganelle se e al p o-apop o ic p o eins eside, igge ing he apop o ic p ocess when eleased in o he cy osol. The pe meabiliza ion o he OMM cons i u es a poin o no e u n in he ac i a ion o his p ocess, whe e he Bcl2 amily o p o eins pa icipa es in i s egula ion [ 164 ]. In e es ingly, ou ne wo k analysis highligh ed he al e a ion on he pe meabili y o memb anes, suppo ing he apop o ic ac i a ion [165]. The OMM mo phology is in luenced by i s in e ac ion wi h he ER, ibosomes, he nucleus, and he cellula cy oskele on [ 3 ]. Fundamen al o he egula ion o mul iple cellula p ocesses a e he mi ochond ial-ER con ac si es [ 164 ]. In ou ne wo k analysis, his in ao ganella in e ac ion was highligh ed as being al e ed in Pa kinson’s disease. Amongs he cellula p ocesses a e: he egula ion o he in acellula calcium le els, mi ochond ial ission, he endowmen o memb anes o phagosomes, and he o ma ion o he in lammasome [ 166 ]. I is now clea how he ER pa icipa es in he ini ia ion o he mi ochond ial ission p ocess. The ER enw aps he mi ochond ia a he cons ic ion si e whe e he dynamin-like p o ein D p1 esponsible o he ission p ocess localizes [ 107 , 167 ]. Addi ionally, ac in polyme iza ion and he ER p o ein in e ed o min 2 (INF2) a e in ol ed in his p ocess [ 38 ]. In e es ingly, ac in ilamen s polyme ized a ound he cons ic ion si es migh cons i u e he pulling o ce o he ission p ocess [ 38 ], and se e al p ocesses ela ed o he ac in cy oskele on we e ound o be al e ed in ou analysis. Addi ionally, he ac in cy oskele on plays a undamen al ole in synap ic esicle sec e ion. The al e a ion o his p ocess a ec s synap ic ansmission in he disease. No only ac in bu also calcium is in ol ed in his p ocess. The egula ion o calcium le els is also dependen on he mi ochond ia-ER c oss alk, and a modi ica ion o i s homeos asis has been epo ed in Pa kinson’s disease [ 168 ]. Mi ochond ial calcium channels display low a ini y o his ion, and o co ec calcium en y in o he mi ochond ia o he o ma ion o he ER-mi ochond ial con ac si es is undamen al [ 169 ]. The ele ance o his in e ac ion has been shown by i s in ol emen in he p og ession o Alzheime ’s disease, whe e i is up egula ed [ 170 ]. When calcium accumula es wi hin he mi ochond ia, oxida i e phospho yla ion An ioxidan s 2018,7, 1 25 o 45 and ATP p oduc ion a e enhanced [ 171 ]. In addi ion, di e en chape ones a e in ol ed in he s abiliza ion o hese con ac si es and could coo dina e signaling be ween mi ochond ia and he ER [ 166 ]. In his di ec ion, we also ound ha he exp ession o he chape one g p78 was al e ed [ 172 ]. The ER-mi ochond ia con ac si es a e also ela ed wi h he ER-s ess esponse, which migh igge apop osis [ 173 ]. This pa hway has also been shown o be ac i e in he con ex o Pa kinson’s disease [ 174 ]. Addi ionally, he calcium eleased by he ER a hese con ac si es migh ac as an ampli ie o he apop o ic pa hway [ 166 ]. Besides, he ission p o ein Fis1 has also been shown o acili a e he clea age o he p o-apop o ic p o ein Bap31 [ 175 ]. In e es ingly, hese con ac si es a e no only ele an o he egula ion o calcium le els, bu also o ROS-media ing signaling [176]. Mo eo e , he ER con ac s wi h he phagosomes and non- unc ional mi ochond ia deg aded by mi ophagy a e ecognized by speci ic OMM p o eins [ 166 ]. MFN2 has also been indica ed as c i ical o au ophagosome o ma ion, and he ER-mi ochond ia in e ac ion is impo an o au ophagosome o ma ion [ 166 , 177 ]. Accumula ing e idence shows ha he ER migh also be in ol ed in he mi ochond ial usion p ocess, since i was shown ha mi o usin2 (MFN2) is necessa y o he e he ing o bo h o ganelles [178]. Rele an o p ope neu onal unc ion is he app op ia e localiza ion o he mi ochond ia wi hin he synap ic e minals, whe e hey can p o ide ATP o exocy osis and egula e calcium le els du ing synap ic ansmission [ 179 ]. Mi ochond ia posi ioning wi hin hese e minals elies no only on mi ochond ial ission [ 180 ], since only small mi ochond ia migh i in o he e minals, bu also in co ec mi ochond ial mo emen along mic o ubules and he ac in cy oskele on [ 164 ]. In his wo k, he ne wo k analysis o cellula componen s and biological pa hways indica ed ha in he con ex o Pa kinson’s disease ac in ilamen s a e a ec ed [ 108 , 112 , 113 ]. In addi ion, dys egula ion o he cellula mic o ubules has been epo ed, namely in he al e a ion o p o eins in ol ed in ubulin ace yla ion. Mos o he d ugs used o induce Pa kinson’s disease modi y mic o ubules, and speci ically, ace yla ion has been shown o a ec he in e ac ion o p o eins wi h he cy oskele on [ 129 ]. Al e a ion o he cellula cy oskele on migh ha e an impac no only on mi ochond ial ission bu also dis ibu ion wi hin neu ons [ 181 – 184 ]. The modi ica ion o he ac in cy oskele on migh also ha e an impac on he egula ion o su ace ecep o dis ibu ion [124], which was highligh ed in he p esen wo k. The ATP p oduced by he mi ochond ia eaches he cy osol by i s ac i e anspo h ough he adenine nucleo ide ansloca o . To p oduce ATP, he p ocesses o he TCA cycle and he espi a o y chain/oxida i e phospho yla ion sys em ac in conjunc ion. The las is loca ed a he IMM. As a esul o he mi ochond ial espi a o y chain de iciency, ATP p oduc ion is educed and ROS a e inc eased, which leads o oxida i e s ess. This inc ease leads o modi ica ions in p o ein, lipids, and DNA wi hin he cells [ 185 ]. Amongs he modi ied lipids, he oxida ion o ca diolipin om he IMM has been epo ed in he con ex o Pa kinson’s disease [ 155 ], and i s oxida ion dis up s he no mal binding o cy och ome c o he memb ane [ 155 ]. Fu he mo e, ER is undamen al o p o iding memb ane lipids o he mi ochond ia [ 186 ], highligh ing again he impo ance o his c oss alk. Phospha idic acid is conside ed a usogenic lipid equi ed o he usion media ed by mi o usins [ 187 ]. Ca diolipin ha e been epo ed o con ol mi ochond ial ission [ 188 , 189 ]. In e es ingly, in he p esen wo k we ound he exp ession o se e al ca diolipin binding p o eins o be modi ied, which migh impac he p ope assembly o he mi ochond ial memb anes. Mo eo e , synap ic mi ochond ia p esen lowe le els o ca diolipin, which has been poin ed ou as a lowe h eshold o he elease o cy och ome c in he apop o ic p ocess [ 164 , 190 ]. I has also been epo ed ha synap ic mi ochond ia p esen highe sensi i i y o he inhibi ion o he mi ochond ial espi a o y chain Complex I [ 191 ]. De achmen o cy och ome c om he memb ane is necessa y o cy och ome c elease o apop o ic ac i a ion and c is ae emodeling [ 27 ]. As discussed abo e, hese undamen al p ocesses ha e been emphasized by he high pe cen age o mi ochond ial-shaping p o eins ound o be al e ed in he con ex o Pa kinson’s disease in con as wi h he p o eins in ol ed in usion and ission. The ER-mi ochond ial connec ion is also impo an o he in lamma o y esponse [ 192 ]. The ac i a ion o he in lammasome migh occu unde an oxida i e s ess scena io, i.e., Pa kinson’s An ioxidan s 2018,7, 1 32 o 45 MIGA1 mi ogua din 1 MIGA2 mi ogua din 2 MINOS1 mi ochond ial inne memb ane o ganizing sys em 1 MINOS2 Mi ochond ial Inne Memb ane O ganizing Sys em 2 MINOS3 Mi ochond ial Inne Memb ane O ganizing Sys em 3 Mi o_shape Mi ochond ial shaping p o eins MITRAC12 Cy och ome c oxidase assembly ac o 3 homolog MPP+ 1-me hyl-4-phenylpy idinium MPRP1 mul id ug esis ance p o ein 1 MPTP 1-me hyl-4-phenyl-1,2,3,6- e ahyd opy idine MT-ATP6 Mi ochond ially Encoded ATP Syn hase 6 MT-ATP8 Mi ochond ially Encoded ATP Syn hase 8 MT-CO1 Mi ochond ially Encoded Cy och ome C Oxidase I MT-CO2 Mi ochond ially Encoded Cy och ome C Oxidase II MT-CO3 Mi ochond ially Encoded Cy och ome C Oxidase III MT-CYB Mi ochond ially Encoded Cy och ome B MTFP1 mi ochond ial ission p ocess 1 m -HSP70 mi ochond ial hea shock p o ein amily A (Hsp70) MTP18 Mi ochond ial ission p ocess p o ein 1 MUL1 mi ochond ial E3 ubiqui in p o ein ligase 1 MULAN Mi ochond ial ubiqui in ligase ac i a o o NFKB 1 My022 ORF name o Mi ochond ial ission p ocess p o ein 1 My025 ORF name o MICOS complex subuni MIC26 My032 ORF name o ATP syn hase subuni d MYL6 myosin ligh chain 6 NAD nico inamide adenine dinucleo ide oxidized NADH nico inamide adenine dinucleo ide educed NBK Bcl-2-in e ac ing kille NDUFA10 NADH:ubiquinone oxido educ ase subuni A10 NDUFA11 NADH:ubiquinone oxido educ ase subuni A11 NDUFA4 NADH Dehyd ogenase (Ubiquinone) 1 Alpha Subcomplex, 4 NDUFS1 NADH:ubiquinone oxido educ ase co e subuni S1 NDUFS3 NADH:ubiquinone oxido educ ase co e subuni S3 NEDD8 neu al p ecu so cell exp essed, de elopmen ally down- egula ed 8 NFE2L2 nuclea ac o , e y h oid 2 like 2 NFKB nuclea ac o kappa-ligh -chain-enhance o ac i a ed B cells NHERF Na(+)/H(+) exchange egula o y co ac o NHE-RF1 NHERF1 Na(+)/H(+) exchange egula o y co ac o NHE-RF1 NHERF-1 p o ein Na(+)/H(+) exchange egula o y co ac o NHE-RF1 NIMA ne e in mi osis gene a NO ni ic oxide Nox1 NADPH oxidase 1 NPM nucleophosmin NPM1 nucleophosmin 1 NRAPGEP Rap guanine nucleo ide exchange ac o 2 NRF1 nuclea espi a o y ac o 1 NRF2 Nuclea ac o e y h oid 2- ela ed ac o 2 OAT o ni hine amino ans e ase OGDH oxoglu a a e dehyd ogenase OIP106 O-linked N-ace ylglucosamine ans e ase in e ac ing p o ein 106 OK/SW-cl.110 ORF name o Phosphoglyce a e kinase 1 OK/SW-cl.56 ORF name o Tubulin be a chain OK/SW-cl.82 ORF name o 40S ibosomal p o ein S15a OMA1 O e lapping Ac i i y Wi h M-AAA P o ease An ioxidan s 2018,7, 1 33 o 45 OMM ou e mi ochond ial memb ane OPA1 Op ic A ophy P o ein 1 OST48 OK/SW-cl.45 synomym o Dolichyl-diphosphooligosaccha ide–p o ein glycosyl ans e ase 48 kDa subuni OTB1 Ubiqui in hioes e ase OTUB1 OTU1 Ubiqui in hioes e ase OTUB1 OTUB1 OTU deubiqui inase, ubiqui in aldehyde binding 1 OXPHOS oxida i e phospho yla ion PARK2 E3 ubiqui in-p o ein ligase pa kin PARL p esenilin associa ed homboid like PD Pa kinson’s disease PD04912 ORF name o Up- egula ed du ing skele al muscle g ow h p o ein 5 PDIA3 p o ein disul ide isome ase amily A membe 3 PDZGEF1 Rap guanine nucleo ide exchange ac o 2 PERC Pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-be a PGAM5 Se ine/ h eonine-p o ein phospha ase PGAM5 PGC1 Pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-alpha PGC1A Pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-alpha PGC1B Pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-be a PGK1 phosphoglyce a e kinase 1 PGKA Phosphoglyce a e kinase 1 PGN pa aplegin PHB p ohibi in PHB2 p ohibi in 2 PIG4 ORF name o MICOS complex subuni MIC60 PIG52 ORF name o MICOS complex subuni MIC60 PIN1 pep idylp olyl cis/ ans isome ase, NIMA-in e ac ing 1 PINK1 PTEN-induced pu a i e kinase 1 PLD6 phospholipase D amily membe 6 PP578 ORF name o Endophilin-B2 PPARGC1 Pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-alpha PPARGC1A Pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-alpha PPARGC1B Pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-be a PPIA pep idylp olyl isome ase A PRDX4 pe oxi edoxin 4 PRELI P o ein O Rele an E olu iona y And Lymphoid In e es PRELID1 PRELI domain-con aining p o ein 1 PRI synonym o Ribonuclease inhibi o PRKN pa kin RBR E3 ubiqui in p o ein ligase PRO0903 ORF name o Se um albumin PRO1708 ORF name o Se um albumin PRO2044 ORF name o Se um albumin PRO2207 ORF name o P esenilins-associa ed homboid-like p o ein PRO2619 ORF name o Se um albumin PRO2675 ORF name o Se um albumin PSARL P esenilins-associa ed homboid-like p o ein PSC8 P o easome componen C8 PSEC0112 ORF name o Mi ogua din 2 PSMA3 p o easome subuni alpha 3 PTPN5 p o ein y osine phospha ase, non- ecep o ype 5 QIL1 synonym o Ch omosome 19 Open Reading F ame 70 RAB14 Ras- ela ed p o ein Rab-14 RAB2 Ras- ela ed p o ein Rab2 RAB2A Ras- ela ed p o ein Rab-2A An ioxidan s 2018,7, 1 34 o 45 RAC1 Ras- ela ed C3 bo ulinum oxin subs a e 1 RAPGEF2 Rap guanine nucleo ide exchange ac o 2 REA synonym o P ohibi in-2 RHO12 as homolog amily membe RHOA as homolog amily membe A RING- ype E3 eally in e es ing new gene ype E3 RNF153 Ring Finge P o ein 153 RNF218 Ring Finge P o ein 218 RNH Ribonuclease inhibi o RNH1 ibonuclease/angiogenin inhibi o 1 ROMO1 eac i e oxygen species modula o 1 ROS eac i e oxygen species RPN1 Ribopho in I RPN2 ibopho in II RPS15A ibosomal p o ein S15a RPS3, OK/SW-cl.26 symbol and ORF name o 40S ibosomal p o ein S3 S100A10 S100 calcium binding p o ein A10 SAM50 So ing and assembly machine y componen 50 homolog SAMM50 So ing and assembly machine y componen 50 homolog SBBI12 ORF name o PRELI domain-con aining p o ein 1 SBP selenium binding p o ein SELENBP1 selenium binding p o ein 1 SF2P32 nuclea splicing ac o SFXN1 side o lexin 1 SH3 SRC Homology 3 Domain SH3GLB1 SH3 domain con aining GRB2 like, endophilin B1 SH3GLB2 SH3 domain con aining GRB2 like, endophilin B2 SIR2L SIR2-like p o ein SIR2L2 SIR2-like p o ein 2 SIRT2 si uin 2 SLC20A4 solu e ca ie amily 20 membe 4 Slc25A solu e ca ie amily 25 SLC25A10 solu e ca ie amily 25 membe 10 SLC25A11 solu e ca ie amily 25 membe 11 SLC25A12 solu e ca ie amily 25 membe 12 SLC25A13 solu e ca ie amily 25 membe 13 SLC25A18 solu e ca ie amily 25 membe 18 SLC25A38 solu e ca ie amily 25 membe 38 SLC9A3R1 solu e ca ie amily 9 (sodium/hyd ogen exchange ), membe 3 egula o 1 SLP2 S oma in-like p o ein 2 SMAD2 Mo he s agains decapen aplegic homolog 2 SMCR7 Smi h-Magenis Synd ome Ch omosomal Region Candida e Gene 7 P o ein SMCR7L Smi h-Magenis Synd ome Ch omosomal Region Candida e Gene 7 P o ein-like SN Subs an ia nig a SPG7 Pa aplegin SSBP single s anded DNA binding p o ein SSBP1 single s anded DNA binding p o ein 1 STOML2 s oma in like 2 SYNJ2 synap ojanin 2 TAZ a azzin TC25 Ras-Like P o ein TC25 TCA ica boxylic acid cycle TCF6 T ansc ip ion ac o TCF6L2 T ansc ip ion Fac o 6-Like 2 An ioxidan s 2018,7, 1 35 o 45 TCP-1-epsilon T-complex p o ein 1 subuni epsilon TFAM ansc ip ion ac o A, mi ochond ial TIM14 Mi ochond ial Impo Inne Memb ane T anslocase Subuni TIM14 TIMM14 T anslocase O Inne Mi ochond ial Memb ane 14 TMSA T opomyosin alpha-1 chain TMSB opomyosin Be a TPD52 umo p o ein D52 TPM1 opomyosin 1 TPM2 opomyosin 2 TPM3 opomyosin 3 TPM4 opomyosin 4 TRAK1 a icking kinesin p o ein 1 TRAK2 a icking kinesin p o ein 2 TRG3 ans o ma ion- ela ed gene 3 TTC11 e a icopep ide Repea Domain 11 TUBA1A ubulin alpha 1a TUBA3 ubulin alpha-3 chain TUBB ubulin be a class I TUBB2C Tubulin be a-4B chain TUBB4B ubulin be a 4B class IVb TUBB5 Tubulin be a chain TUFM Tu ansla ion elonga ion ac o , mi ochond ial UniP o Uni e sal P o ein Resou ce UNQ1866/PRO4302 ORF name o MICOS complex subuni MIC26 UNQ1868/PRO4304 ORF name o ATP-dependen zinc me allop o ease YME1L1 UNQ655/PRO1286 ORF name o Ubiquinol-cy och ome-c educ ase complex assembly ac o 3 UNQ696/PRO1341 ORF name o Se um albumin UNQ8193/PRO23204 ORF o MICOS complex subuni MIC27 UQBP Ubiquinol-cy och ome c educ ase complex 14 kDa p o ein UQCC3 ubiquinol-cy och ome c educ ase complex assembly ac o 3 UQCR10 Ubiquinol-Cy och ome C Reduc ase, Complex III Subuni X UQCR11 Ubiquinol-Cy och ome C Reduc ase, Complex III Subuni XI UQCRB ubiquinol-cy och ome c educ ase binding p o ein UQCRC1 ubiquinol-cy och ome c educ ase co e p o ein 1 UQCRC2 ubiquinol-cy och ome c educ ase co e p o ein 2 UQCRFS1 ubiquinol-cy och ome c educ ase, Rieske i on-sul u polypep ide 1 UQCRFS1 ubiquinol-cy och ome c educ ase, Rieske i on-sul u polypep ide 1 UQCRFS1P1 ubiquinol-cy och ome c educ ase, Rieske i on-sul u polypep ide 1 pseudogene 1 UQCRFSL1 Ubiquinol-cy och ome c educ ase Rieske i on-sul u subuni pseudogene 1 UQCRH ubiquinol-cy och ome c educ ase hinge p o ein UQCRQ ubiquinol-cy och ome c educ ase complex ubiquinone-binding p o ein QP-C USMG5 Up- egula ed du ing skele al muscle g ow h p o ein 5 VAT1 esicle amine anspo 1 VCP alosin con aining p o ein VDAC1 Vol age-dependen anion-selec i e channel p o ein 1 VDAC2 ol age dependen anion channel 2 VDAC3 ol age dependen anion channel 3 VDAC Vol age-dependen anion-selec i e channel VIM imen in VISA Vi us-induced-signaling adap e YME1L YME1-like p o ein 1 YME1L1 YME1-like p o ein 1 YWHAE y osine 3-monooxygenase/ yp ophan 5-monooxygenase ac i a ion p o ein epsilon YWHAZ y osine 3-monooxygenase/ yp ophan 5-monooxygenase ac i a ion p o ein ze a An ioxidan s 2018,7, 1 36 o 45 Re e ences 1. 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