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
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