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Jou nal: T ends in Cell Biology
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Da e and olume: 2025 Jan;35(1):33-45.
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doi: 10.1016/j. cb.2024.08.007.
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Ti le: C oss alk be ween mi ochond ia-ER con ac si es and he apop o ic
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machine y as a no el heal h me e
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Au ho s: Al a o La añaga-SanMiguel, No a Bengoa-Ve gnio y, Hec o Flo es-
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Rome o
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PMID: 39379268
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C oss alk be ween Mi ochond ia-ER con ac si es and apop o ic machine y as
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a no el heal h-me e
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Al a o La añaga-SanMiguel1, No a Bengoa-Ve gnio y1, 2, 3, 4 and Hec o Flo es-
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Rome o1-2,*
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1. Achuca o Basque Cen e o Neu oscience, Leioa, Spain.
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2. Ike basque, Basque Founda ion o Science, 48013, Bilbao, Spain.
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3. Ox o d Pa kinson’s Disease Cen e and Depa men o Physiology, Ana omy and
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Gene ics, Uni e si y o Ox o d, Sou h Pa k Road, Ox o d OX1 3QU, UK.
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4. Uni e si y o he Basque Coun y (UPV/EHU), Depa men o Neu oscience,
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Leioa, Spain.
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* co espondence: [email p o ec ed] (Flo es-Rome o, H)
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Keywo ds: MERCS, MAMs, Apop osis, In lamma ion, Neu odegene a ion, cance .
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Abs ac
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Mi ochond ia-ER Con ac Si es (MERCS) unc ion as ansien signalling pla o ms ha
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egula e essen ial cellula unc ions. MERCS a e en iched in speci ic p o eins and
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lipids ha connec mi ochond ia and he ER oge he , modula ing hei ac i i ies.
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Dys egula ion o MERCS is associa ed wi h se e al human pa hologies, including
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Alzheime ’s disease, Pa kinson’s disease and cance . BCL-2 amily p o eins can
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loca e a MERCS and con ol essen ial cellula unc ions such as calcium signalling
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and au ophagy in addi ion o hei ole in mi ochond ial apop osis. Mo eo e , he BCL-
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2-media ed apop o ic machine y was ecen ly ound o igge cGAS/STING pa hway
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ac i a ion and p oin lamma o y esponse, a ecognized hallma k in hese diseases ha
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equi es mi ochond ia-ER in e play. This Opinion a icle unde sco es he pi o al ole o
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MERCS in egula ing essen ial cellula unc ions, ocusing on hei c oss alk wi h BCL-
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2 amily p o eins and discusses how hei dys egula ion is linked o disease.
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MERCS, undamen al dynamic s uc u es equi ed o cellula homeos asis
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The in e ace be ween cellula o ganelles is inc easingly ecognized as a pi o al
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pla o m go e ning essen ial biological p ocesses in euka yo ic cells. Speci ically, he
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con ac si es be ween mi ochond ia ou e memb ane (MOM) and he endoplasmic
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e iculum (ER), e e ed o as Mi ochond ia-Endoplasmic Re iculum Con ac Si es
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(MERCS) also known as mi ochond ia-associa ed ER memb anes (MAMs), ep esen
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mos ly ansien dynamic modules en iched in speci ic lipids and specialized p o eins
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ha de ine hei s uc u e and unc ions (see Glossa y) [1,2]. These ER-mi ochond ial
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junc ions, whe e he in e o ganella dis ance anges be ween 10 and 80 nm, se e as
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key loca ions o calcium (Ca2+) signalling, lipid ans e , and play c ucial oles in
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cellula bioene ge ics, p o eos asis, mi ochond ial quali y con ol, au ophagy and
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apop o ic cell dea h [3,4].
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Resea ch employing echniques such as li e-cell luo escence and elec on
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mic oscopy has e ealed se e al ea u es o hese igh ly e he ed, ye sepa a e,
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memb ane s uc u es. I is becoming clea ha he numbe o con ac s, he su ace
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a ea o con ac and he in e o ganella dis ance a e h ee undamen al aspec s o
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MERCS media ed signalling a ec ing i s igge ing, ampli ica ion and kine ics [4,5].
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Since bo h he ER and mi ochond ia a e dynamic o ganelles, i is unclea how hese
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con ac a eas a e es ablished. In yeas , MERCS a e main ained h ough a complex o
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known composi ion called ER-mi ochond ia encoun e s uc u e, ERMES [6]. Howe e ,
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in mammals he molecula a chi ec u e o MERCS o ma ion and s abiliza ion is mo e
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in ica e and poo ly unde s ood [7]. A hand ul o p o eins ha e been desc ibed o
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main ain MERCS, ac ing like memb ane- e he s, including inosi ol 1,4,5- iphospha e
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ecep o s (IP3Rs) [8] oge he wi h VDACs (Vol age dependen anion channels) [9];
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he esicle-associa ed memb ane p o ein B (VAPB) associa ed o PTPIP51 (p o ein
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y osine phospha ase-in e ac ing p o ein-51) [10], mi o usin-2 (MFN2) and ela ed
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iso o ms [11,12], B-cell ecep o -associa ed p o ein-31 (BAP-31) [13] and PDZ
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domain-con aining p o ein 8 (PDZD8) [14] (Figu e 1).
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Each o hese MERCS- e he s exhibi dis inc cha ac e is ics and a e in ica ely linked
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o speci ic cellula unc ions and egula ed by adap o s exp essed in esponse o
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di e se s imuli. Impo an ly, he p o eins wi hin hese con ac si es a e nei he exclusi e
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no speci ic o MERCS, which p esen s echnical challenges o unde s anding hei
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exac na u e. Mo eo e , wi hin a single MERCS, mul iple specialized in e ac ion
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domains may coexis , u he unde sco ing hei dynamic na u e being able o emodel
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in esponse o changes in he en i onmen and mee he me abolic needs o he cell
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[15]. Fo example, IP3Rs a e key media o s o ER-mi ochond ia Ca2+ homeos asis,
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ac ing as channels o Ca2+ anspo . IP3R o ms a e ame ic complex wi h VDAC,
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he molecula chape one GRP75 (Glucose- egula ed p o ein 75) and he deglycase
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DJ-1, o modula e he Ca2+ ans e om he ER o he mi ochond ial ma ix, using he
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mi ochond ial calcium unipo e (MCU) [16–18], which can esul in s imula ion o K ebs
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cycle enzymes and OxPhos [19,20]. The VAPB-PTPIP51 e he complex is ela ed o
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Ca2+ signalling as well, bu also o al e a ions in mi ochond ial mo phology and
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agg ega ion [10,21]. Deple ion o ei he VAPB o PTPIP51 leads o he dis up ion o
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MERCS, pe u ba ion o Ca2+ anspo and au ophagy s imula ion [10,22]. Some
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au ho s also epo ed ha MFN2 and i s splicing a ian s can ac as a physical e he
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s abilizing he con ac be ween bo h o ganelles, a ou ing lipid ans e and egula ing
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mi ochond ial dynamics [11,12]. Howe e , his emains a con en ious opic wi hin he
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ield [23–26]. Finally, BAP-31 has been shown o modula e mi ochond ial oxygen
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consump ion, au ophagy and apop o ic cell dea h [13]. These s udies collec i ely
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e eal ha MERCS- e he s ha e dis inc oles in egula ing speci ic cellula p ocesses.
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While hei in es iga ion is echnically demanding, i is c ucial o unco e ing hei i al
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con ibu ions o main aining cellula homeos asis.
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These di e se MERCS-media ed unc ions a e known o be dys egula ed in mul iple
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human pa hologies including cance and neu odegene a i e diseases such as
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Alzheime ’s disease (AD) and Pa kinson’s disease (PD) [3,27–29]. In e es ingly, ecen
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e idence un a elled ha MERCS a e al e ed du ing cellula senescence, which could
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media e hei impac on aging and age- ela ed diseases [30]. Howe e , he d i ing
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cellula mechanisms behind hese oles emain poo ly de ined. P o eins belonging o
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he BCL-2 amily, which a e conside ed he main egula o s o mi ochond ial apop osis
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[31–34], a e key egula o s o MERCS-associa ed unc ions and s ongly con ibu e o
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he cell dea h imbalance obse ed in hese age- ela ed diseases. In his Opinion
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a icle, we will discuss he ole o MERCS in heal h and disease, wi h a no el
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pe spec i e emphasizing he c oss alk be ween MERCS and he BCL-2 media ed
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apop o ic machine y, egula ing cell dea h and in lamma ion, and highligh ing non-
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apop o ic BCL-2 oles in cellula homeos asis.
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BCL-2 and MERCS, a no el cellula heal h-me e ?
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BCL-2 amily p o eins o m a complex in e ac ion ne wo k in which mi ochond ial and
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ER memb anes play a key modula o y ole. These p o eins a e ypically classi ied in o
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h ee main g oups: i) he an i-apop o ics (e.g. BCL-2, BCL-XL, o MCL1), also known
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as gua dians, ha p e en MOM pe meabiliza ion (MOMP) and consequen ly
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apop osis; ii) he p oapop o ic mul idomain o e ec o s (e.g. BAX and BAK), which
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di ec ly induce MOMP and apop osis by o ming a po e a he mi ochond ia; and iii) he
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BH3-only p o eins (e.g. BIM, BID o BAD), which igge apop osis by ei he blocking
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an i-apop o ics o di ec ly ac i a ing e ec o s [35–38].
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Du ing apop osis, BAX and BAK con e ge a he mi ochond ia o o m he apop o ic
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po e, inducing MOMP and he subsequen elease o p o-apop ogenic ac o s o he
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cy osol [36]. The unable p o ein:lipid na u e o he o med po es, allows he passage
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o small molecules such as cy och ome c o SMAC, bu also la ge molecules, such as
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mi ochond ial DNA (m DNA) [39–42]. Once in he cy osol, eleased cy och ome c and
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SMAC p omo e he assembly o he apop osome, inducing caspase ac i a ion and
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apop o ic cell dea h (Figu e 2). Impo an ly, suble hal ac i a ion o his machine y, wi h
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only pa ial elease o he mi ochond ial con en , a phenomenon ha is known as
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mino i y MOMP, is associa ed wi h a suble hal caspase ac i a ion, damage in he
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nuclea DNA and genomic ins abili y [43]. Released m DNA in he cy osol, is
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ecognised by nucleic acid senso s like cGAS (cy osolic cyclic GMP–AMP syn hase).
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cGAS ac i a ion leads o he syn hesis o 2′3′ cyclic GMP–AMP (cGAMP), which
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ac i a es he ER-localized S imula o o in e e on genes (STING). Ac i a ed, STING
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ansloca es o he Golgi, inducing TANK-binding kinase 1 (TBK1) and In e e on
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egula o y ac o 3 (IRF3) phospho yla ion, inducing he exp ession o ype I in e e ons
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[44–46].
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O no e, his p o-in lamma o y esponse is ini ia ed wi hin he mi ochond ia bu elies
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on he ER o i s ampli ica ion, unde sco ing he ole o MERCS (Figu e 2). In his
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ega d, knock down o he MERCS e he VAPB subs an ially dec eases in e e on-
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media ed in lamma ion [47] and STING deple ion po en ia es VDAC2/GRP75-
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media ed MERCS o ma ion impai ing mi ochond ial unc ion [48]. Indeed,
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mi ochond ial VDAC2 was ecen ly iden i ied as a new STING binding pa ne able o
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egula e BAX/BAK apop o ic ac i i ies [48–50]. This highligh s he impo ance o he
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c oss alk be ween MERCS- e he s, BCL-2 p o eins and STING machine y. Mo eo e ,
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du ing in ec ion BAX can in e ac wi h IRF3, impac ing STING signalling and
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in lamma ion [51–53]. In addi ion, MAVS (mi ochond ial an i i al-signalling p o ein) and
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he nucleo ide-binding oligome iza ion domain-like ecep o p o ein 3 (NLRP3),
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esponsible o in lammasome ac i a ion, in e ac a MERCS, sugges ing ha hese
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con ac a eas also play a ole in inna e immuni y [54–56].
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On he o he hand, he BCL-2 in e ac ion ne wo k and downs eam cascades can be
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in luenced by MERCS-media ed lipid anspo . O no e, he majo i y o mi ochond ial
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lipids, including phospholipids, sphingolipids, and choles e ol, a e syn hesized in he
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ER and hen ans e ed o he mi ochond ia ia MERCS [57,58]. Despi e hei mino
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p esence a he mi ochond ia, sphingolipids (e.g. ce amide and sphingosine-1P) ha e
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been epo ed o play a c ucial ole in ine- uning he apop o ic machine y: ce amide is
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equen ly associa ed wi h p omo ing BAX/BAK-dependen apop osis, while
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sphingosine-1P is linked o cell su i al ( e iewed in [59]). Addi ionally, ele a ed le els
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o choles e ol a he mi ochond ia a e co ela ed o impai ed BAX ac i a ion and cell
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su i al [58,60]. In addi ion, ca diolipin (CL) plays a key ole du ing apop osis in he
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mi ochond ial a ge ing o BAX [61], i s oligome iza ion [62], and he apop o ic po e
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o ma ion [63]. Impo an ly, CL (which is essen ial o mi ochond ial c is ae
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main enance) ep esen s a ound 4-8% o he MOM lipids, bu is highly en iched a
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MERCS wi h 25% o he o al lipid con en [64], highligh ing he impo ance o hese
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s uc u es o BAX ac i a ion and he apop o ic po e o ma ion.
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In addi ion, BCL-2 amily p o eins a e known o egula e essen ial MERCS-associa ed
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ac i i ies such as Ca2+ signalling, mi ochond ial dynamics, bioene ge ics, he un olded
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p o ein esponse (UPR), mi ochond ial quali y con ol and au ophagy ( e iewed in
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[34,65]). Fo example, he an iapop o ic p o ein BCL-2 and p oapop o ic BOK, in e ac
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wi h he MERCS- e he IP3R, displaying opposing oles in Ca2+ egula ion, as bo h he
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up egula ion o BCL-2 and low le els o BOK a e linked o limi ed Ca2+ luxes o he
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mi ochond ia [66,67]. O he s udies suppo he idea ha BOK in e ac s wi h IP3R a
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MERCS modula es p ima ily mi ochond ial dynamics and bioene ge ics [68].
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An iapop o ic membe s such as BCL-XL, MCL-1 and BCL-B a e also epo ed o bind
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o IP3R limi ing Ca2+ anspo o he mi ochond ia [69–71]. Rega ding he UPR,
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se e al BCL-2 amily p o eins unc ion as s ess heos a s [72,73]. The BH3-only
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p o eins BID, PUMA, NOXA, BAD and BIM, a e ansc ip ionally and pos -
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ansla ionally induced unde acu e ER s ess [74–77] and he apop o ic e ec o BOK
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ansloca es o he mi ochond ia inducing MOMP [67,78,79]. BCL-2 amily membe s
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a e also implica ed in egula ing mi ochond ial dynamics, in e ac ing wi h MFN2 and
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he dynamin- ela ed p o ein 1 (DRP1), a ec ing mi ochond ial usion and ission e en s
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[80–82]. Finally, BCL-2 is epo ed o in e ac wi h Beclin-1 impai ing au ophagy [83].
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O e all, independen s udies epo a con inuous c oss alk be ween MERCS esiden
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p o eins and BCL-2 amily membe s which is esponsible o ine- uning hei
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espec i e ac i i ies and in luencing cell a e. Al e a ions in he no mal unc ion o bo h
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MERCS and BCL-2 amily p o eins a e equen ly associa ed wi h se e e human
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diseases. Howe e , due o he dynamic na u e o hese s uc u es and hei
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o e lapping unc ions, i is complica ed o disce n whe he al e a ions in MERCS a e a
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cause o a consequence o he disease. In he ollowing sec ions, we will explo e
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a ia ions in he composi ion o MERCS in ela ion o cance , AD, and PD. These a e
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age- ela ed diseases, in which al e a ions in MERCS, BCL-2 p o eins, and
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cGAS/STING-induced in lamma ion coexis , and so hei in e play could play c ucial
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p e iously o e looked oles in disease.
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MERCS as a c ucial axis in human disease
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MERCS and BCL-2 p o eins in Cance : Twis ing homeos asis owa ds p oli e a ion.
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The communica ion be ween he ER and mi ochond ia plays a c ucial ole in cance
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de elopmen and p og ession. MERCS se e as signalling pla o ms ha a e in ol ed
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in ewi ing no mal cellula p ocesses owa ds malignancy (Figu e 3A-B). Abe an
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exp ession o mislocaliza ion o MERCS- esiden p o eins is obse ed in se e al ypes
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o cance . Fo ins ance, he o e exp ession and inc eased MERCS localiza ion o ER
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s ess senso s like ER oxido educ in 1-alpha (ERO1-α) and RNA-dependen p o ein
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kinase (PKR)-like ER kinase (PERK), a e implica ed in umou ini ia ion, p og ession,
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and esis ance o chemo he apy [84,85]. In b eas cance , he s ess-ac i a ed
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chape one sigma-1 ecep o (Sig1R) exhibi s highe exp ession and inc eased
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MERCS localiza ion in me as a ic cance cells compa ed o no mal issues, modi ying
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IP3R-media ed Ca2+ dynamics and p omo ing cell in asi eness and mig a ion [86–88].
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Con e sely, educed exp ession o he MERCS- e he MFN2 is co ela ed wi h wo se
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p ognosis in colon and enal cance sub ypes [81,89], which aken oge he highligh
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an o e a ching ole o MERCS in cance .
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Rega ding BCL-2 amily p o eins, he educed apop osis, excessi e p oli e a ion and
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umou chemo he apy esis ance obse ed in cance , a e ce ainly linked o al e ed
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signal c oss alk be ween he ER and he mi ochond ia [90,91]. Fo example, he
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up egula ion o an iapop o ic BCL-2 and BCL-XL is co ela ed wi h a educ ion in IP3R-
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media ed Ca2+ signalling and educed cell dea h in se e al cance ypes [66,92,93].
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P oapop o ic BOK also epo ed o in e ac wi h he IP3R, is dele ed ac oss se e al
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cance ypes and associa ed wi h impai ed cell dea h [94]. On he o he hand,
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mi ochond ial lipid composi ion, ine- uned by mi ochond ia-ER communica ion, is also
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al e ed in cance condi ions. Fo example, ele a ed choles e ol le els a he
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mi ochond ia a e linked o educed ac i a ion o he p oapop o ic BCL-2 membe BAX
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and cell su i al in cance [60,95]. Mo eo e , dys egula ion o CL and ce amide
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me abolism, key lipids in p omo ing BAX/BAK ac i a ion and mi ochond ial apop osis
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has been obse ed in se e al ypes o cance ( e iewed in [96,97]).
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Finally, BAX/BAK-media ed cGAS/STING- egula ed immune esponses can impac
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mos o he aspec s associa ed wi h umo igenesis, om malignan cell ans o ma ion
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o me as asis ( e iewed in [98]). In his ega d, BAX/BAK induced mino i y MOMP wi h
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pa ial ac i a ion o he apop o ic machine y has been linked o he gene a ion o
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genomic ins abili y, causing a cell dea h esis ance pheno ype ha includes
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coloniza ion and me as asis in i o [99], and d i es agg essi e ea u es in esidual
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cance cells [100]. On he o he hand, suble hal BAX/BAK-dependen cGAS/STING
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signalling ac i a ion can induce a ch onic senescence-associa ed sec e o y pheno ype
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(SASP) [101]. Al hough o iginally belie ed o hal cance p og ession due o hei
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cha ac e is ic g ow h a es , senescen cells emain me abolically ac i e and sec e e
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di e en in lamma o y agen s, gene a ing a mic oen i onmen ha can p omo e umou
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g ow h [102].
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An imbalance in MERCS-media ed unc ions and BCL-2 amily p o eins can he e o e
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lead o a ple ho a o cance -d i ing p ocesses, bo h wi hin cells and in hei
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su oundings, including umou ini ia ion, p og ession, su i al, and me as asis. This
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unde sco es he impo ance o main aining MERCS homeos asis o pu a i ely p edic
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and p e en cance - ela ed ea u es.
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MERCS, BCL-2 p o eins and Alzheime ’s Disease: P oximi y ails o e eal he whole
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pic u e.
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Alzheime ’s Disease (AD) is he mos p e alen neu odegene a i e diso de wo ldwide,
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leading o cogni i e de ici s and demen ia [103]. Cen al o AD diagnosis is he
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o ma ion o in acellula neu o ib illa y angles composed o hype phospho yla ed au
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and ex acellula plaques consis ing o amyloid-β (Aβ) pep ides [103]. These
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agg ega es and he subsequen in lamma o y p ocess a e hough o lead o neu onal
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dys unc ion and loss. The γ-sec e ase complex, comp ising p esenilin 1 (PS1) o
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p esenilin 2 (PS2) as ca aly ic subuni s, plays a c ucial ole in he clea age o amyloid
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p ecu so p o ein (APP), yielding Aβ agmen s. Impo an ly, bo h APP and he γ-
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sec e ase complex ha e been iden i ied a MERCS in i o, sugges ing a po en ial
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in ol emen o MERCS in AD pa hogenesis [104–107] (Figu e 3C).
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Mu an o ms o APP, PS1 and PS2 enhance ER–mi ochond ial e he ing, a ec ing
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Ca2+ dynamics and lipid me abolism, con ibu ing o mi ochond ial dys unc ion and
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neu onal cell dea h which a e obse ed du ing AD [108–110]. Fo example, mu an s o
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PS2 modula e Ca2+ ans e o he mi ochond ia h ough in e ac ion wi h MFN2 [108].
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S udies in MEF cells lacking MFN2, showed diminished MERCS and educed
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in e o ganella choles e ol a icking [110]. Howe e , in appa en con adic ion o i s
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pu a i e e he ing unc ion, knocking down MFN2 has also been associa ed wi h an
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inc ease in mi ochond ia-ER con ac s, al e ed mi ochond ial Ca2+ ans e and educed
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APP p ocessing [111]. Simila disc epancies exis ega ding he pu a i e ole ha Aβ
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exe s o e MERCS. In i o s udies in hippocampal neu ons om AD a models
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indica e a educ ion in MERCS upon Aβ exposu e, associa ed wi h diminished lipid
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me abolism and al e a ions in he mi ochond ial lipidome [112]. In acco dance wi h his
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inding, in D osophila models, o ced exp ession o an a i icial linke ha enhances
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MERCS in i o escues locomo ion and p olongs he su i al in AD models [113].
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Howe e , o he s udies in p ima y hippocampal neu ons show ha Aβ ea men
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inc eases MERCS and dis up s Ca2+ homeos asis [114]. This was also he case in
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ib oblas s om bo h amilial and spo adic AD pa ien s ha showed an inc ease in ER-
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mi ochond ia e he ing wi h MERCS dys unc ion, including al e a ions in phospholipid
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and choles e ol me abolism [110]. While some o hese opposing esul s a e di icul o
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in e p e , hey a e pe haps no en i ely unexpec ed as MERCS a e mos ly dynamic and
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plas ic cell signalling s uc u es and as such will highly depend on he s udied model
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and disease snapsho . Impo an ly, s udies in AD models ha e shown changes in he
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MERCS p o eome p eceding he onse o cogni i e symp oms, indica ing a po en ial
278
ole o MERCS dys egula ion in d i ing disease p og ession [115], and unde sco ing
279
hei ole in AD.
280
A MERCS, an iapop o ic BCL-2 plays a c ucial ole in Ca2+ homeos asis and cell
281
su i al, and i s down egula ion is associa ed wi h AD [116]. Reduced exp ession
282
le els o o he an iapop o ic p o eins such as BCL-XL, and MCL1, alongside ele a ed
283
le els o p oapop o ic p o eins like BIM o BAX, il ing he BCL-2 in e ac ion ne wo k
284
owa ds dea h, is also associa ed wi h AD and he neu onal dea h obse ed du ing
285
disease p og ession [117] (and e iewed in [116]). Finally, ecen indings indica e ha
286
ac i a ion o he inna e immune cGAS-STING pa hway con ibu es o AD in 5×FAD
287
mice [118]. In his s udy, cGAS KO mice we e signi ican ly p o ec ed om cogni i e
288
impai men , amyloid-β pa hology, neu oin lamma ion, and o he aspec s associa ed
289
wi h AD [118]. Whils he speci ic impac o BCL-2 p o eins on he cGAS-STING
290
pa hway ela ed o AD pa hogenesis emains poo ly desc ibed, ecen e idence linked
291
AD isk alleles wi h BAX-dependen m DNA elease and ele a ed mic oglial cGAS
292
pa hway ac i a ion [119], which again poin s owa ds an in e play be ween MERCS
293
and apop o ic machine y p o eins in AD. Non-cell au onomous e ec s downs eam o
294
MERCS dys egula ion may be pa icula ly impo an in AD gi en i s s ong glial and
295
pe iphe al componen s.
296
297
MERCS and BCL-2 in Pa kinson’s Disease: Mi ophagy o he escue
298
Pa kinson’s Disease (PD) is a p og essi e neu odegene a i e diso de cha ac e ized
299
by he loss o neu ons, pa icula ly in he subs an ia nig a pa s compac a (SNpc),
300
leading o symp oms such as emo s, dyskinesia and demen ia [120]. The dis up ion
301
o MERCS is associa ed wi h PD pa hogenesis, he eby a ec ing he communica ion
302
be ween mi ochond ia and he ER (Figu e 3D). Indeed, α-Synuclein, a p o ein which
303
is able o agg ega e and is ound in Lewy bodies, which a e a hallma k o PD, is
304
localized a MERCS and implica ed in hei mal unc ion [121]. Wild ype α-Synuclein as
305
well as i s PD-associa ed mu an s A30P and A53T a e shown o a ge MERCS h ough
306
he in e ac ion wi h he VAPB/PTPIP51 e he -complex, and ye he impac o he
307
di e en mu a ions emains unde in es iga ion [122,123]. None heless, he
308
impai men o VAPB and PTPIP51 e he ing ac i i y is associa ed wi h neu onal
309
synap ic dys unc ion [124]. Fu he mo e, gene ic mu a ions associa ed wi h amilial PD
310
such as hose in DJ-1, PINK1, and Pa kin, p o eins ha a e loca ed a MERCS
311
[18,82,125]. Mu a ions in DJ-1 impai i s ole in main aining Ca2+ homeos asis and
312
acili a ing ER-mi ochond ial e he ing, al e ing he IP3R-GRP75-DJ1-VDAC complex
313
[17,18]. Impo an ly, abla ion o DJ-1 inc eases mi ochond ia-ER dis ance, he eby
314
educing mi ochond ia-ER communica ion, which can be escued by wild- ype DJ-1
315
bu no by PD- ela ed mu an s [17,18]. In addi ion, mu a ions in he mi ophagy
316
media o s PINK1 and Pa kin, as well as in hei associa ed p o eins MIRO1 and MFN2,
317
a e also ela ed o MERCS dys egula ion in PD [82,126–128]. Pa kin exp ession
318
inc eases MERCS in HeLa cells, he eby enhancing Ca2+ signalling and ATP
319
p oduc ion [126] and con e sely, loss o Pa kin in human ib oblas s leads o a
320
dec ease in MERCS [82]. In Pa kin KO mice and pa ien s wi h Pa kin mu a ions, he
321
absence o Pa kin, howe e , was linked o inc eased connec i i y be ween
322
mi ochond ia and he ER along wi h inc eased Ca2+ anspo [127]. Mu a ions in
323
MIRO1 a e associa ed wi h dec eased MERCS and impai ed Ca2+ anspo o he
324
mi ochond ia in PD pa ien s [128]. Fu he mo e, he MERCS e he MFN2 ge s
325
phospho-ubiqui inyla ed in Pa kin/Pink1 dependen mi ophagy. Mu a ions ha inhibi
326
his pos ansla ional modi ica ion a e epo ed o dec ease MERCS, sugges ing loss
327
o Pa kin o ubiqui ina ion-p e en ing mu a ions in MFN2, educed MERCS and
328
mi ophagy [82]. Impo an ly, ecen s udies ha e unde sco ed he impo ance o
329
mi ophagy in mi iga ing cy osolic m DNA-dependen ac i a ion o cGAS/STING
330
in lamma ion du ing aging signalling [129], a pa hway implica ed in accele a ing
331
neu odegene a ion p og ession in a mouse model o PD [130]. As p e iously
332
men ioned, while he associa ion be ween MERCS and PD is i e u able, con adic o y
333
indings could be explained by he dynamic and ansien na u e o MERCS associa ed
334
signalling, which highligh s he need o ca e ully in e p e hese indings. This is
335
especially ele an o PD, which is igh ly associa ed wi h mi ochond ial mal unc ion,
336
h ough bo h gene ics and oxic exposu e o compounds such as o enone.
337
BCL-2 p o eins con ibu e o de ec s in mi ophagy, neu onal cell dea h and he
338
pa hogenesis o PD ( e iewed in [131]). Al hough he p ecise molecula mechanisms
339
emains deba ed o PD, BCL-2 has been associa ed wi h MERCS localised
340
PINK1/Pa kin and Beclin-1 o media e au ophagy [125,131]. Exp ession le els o BCL-
341
2 as well as o he an iapop o ic p o eins such as BCLXL a e signi ican ly dec eased in
342
PD pa ien s, wi h a nega i e co ela ion obse ed wi h disease du a ion and se e i y
343
[132,133]. Consis en ly, accumula ion o he p oapop o ic BAX has been obse ed in
344
neu ons o he SNpc in pos -mo em b ains om PD pa ien s [134], and in neu ons
345
con aining Lewy bodies [135]. Despi e he speci ic impac o BCL-2 amily p o eins
346
di ec ly ac i a ing cGAS-STING pa hway and subsequen in lamma ion, his has no
347
ye been desc ibed in PD; hei ole in mi ophagy could play an impo an ole by
348
silencing his pa hway [129,131]. Indeed, es o ing au ophagy h ough modula ion o
349
BCL-2, has been al eady p oposed o PD ea men [136].
350
Concluding Rema ks
351
The e is a clea link be ween al e a ions in MERCS and impo an human pa hologies.
352
He e, we discuss cance , PD, and AD, which a e becoming inc easingly p e alen in
353
ou socie y. En iched wi h s imuli-speci ic p o eins and lipids, MERCS play a i al ole
354
in a ious cellula unc ions such as Ca2+ signalling, lipid ans e , ROS p oduc ion and
355
mi ophagy unde heal hy condi ions. This complexi y poses a challenge in disce ning
356
whe he hei dys egula ion is a po en ial cause o a consequence o he disease.
357
Howe e , some s udies al eady sugges MERCS dynamics and composi ion p eceding
358
he onse o cogni i e symp oms, indica ing a po en ial ole o MERCS dys egula ion
359
in d i ing disease p og ession. The e o e, designing molecules ha imp o e
360
mi ochond ia-ER communica ion could lead o new he apeu ic oppo uni ies. Despi e
361
hei undamen al impo ance, he e is signi ican con o e sy su ounding he
362
composi ion o MERCS. This is likely due o echnical challenges associa ed wi h
363
s udying hese dynamic s uc u es in i o, he use o di e en expe imen al models,
364
and he low empo al esolu ion du ing hei cha ac e iza ion. Some disease
365
de elopmen s may ake yea s o e en decades o mani es , sugges ing ha analysing
366
MERCS a a single ime poin may be insu icien and ha some o he obse a ions
367
could be an epiphenomenon. Unde s anding he sequence o e en s would p o ide
368
no only mechanis ic de ails bu could also p o ide a b oade window o ea men .
369
BCL-2 amily p o eins, he main egula o s o mi ochond ial apop osis, a e esponsible
370
o se e al MERCS- ela ed unc ions and hey a e also associa ed wi h he imbalance
371
in apop o ic cell dea h obse ed in cance , PD, and AD. Recen ly, he mi ochond ial
372
apop o ic machine y has been associa ed o he elease o m DNA and he ac i a ion
373
o he cGAS/STING pa hway. As his signalling equi es mi ochond ia-ER
374
communica ion, i sugges s ha MERCS could o ches a e o sense his pa hway p io
375
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845–861
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Figu e 1.
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Figu e 2.
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Figu e 3.
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Highligh s
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- MERCS se e as signaling hubs in ol ed in i al cellula p ocesses such as calcium
882
signaling, lipid me abolism, au ophagy, and apop osis.
883
- Al e a ions in MERCS dynamics and composi ion a e closely associa ed wi h se e e
884
human diseases such as neu odegene a i e diso de s and cance .
885
- The BCL-2 p o ein amily, p ima y egula o s o mi ochond ial apop osis and key
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playe s in main aining cellula homeos asis, ope a e a MERCS o ul ill essen ial
887
cellula unc ions.
888
- Apop o ic machine y-induced cGAS-STING pa hway ac i a ion and p oin lamma o y
889
signaling, equi es mi ochond ia-ER communica ion and is a ec ed in cance , AD and
890
PD.
891
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Ou s anding ques ions
893
- Is he composi ion o MERCS ailo ed o speci ic issues o cell- ypes, adap ing o
894
speci ic needs? Do di e en MERCS e he s wo k simul aneously? Do hey compe e
895
o he same loca ions? Can hey exhibi edundancy? Wha is hei con o ma ional
896
s a us when hey a e no b idging in e o ganella connec ions?
897
- A e changes in he s uc u e o unc ion o MERCS a po en ial cause o disease, a
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esul o disease, o a e hey adap i e adjus men s o compensa e cellula imbalances
899
du ing disease de elopmen ? Do hose changes emain cons an h oughou he en i e
900
p ocess? Could es o ing MERCS unc ion e ec i ely amelio a e disease p og ession?
901
- Can co ela ions be es ablished be ween dis up ions in MERCS- esiden p o eins and
902
diseases, po en ially leading o hei use as diagnos ic bioma ke s? Could he
903
in e ac ions be ween BCL-2 amily p o eins and MERCS unc ions be le e aged o
904
assess o e all cellula heal h o suscep ibili y o disease?
905
- Is he ac i a ion o suble hal apop o ic machine y causing ch onic in lamma ion and
906
cellula s ess, con ibu ing o he excessi e accumula ion o Aβ o α-synuclein
907
obse ed in AD and PD o a consequence o hese pa hologies? Would inhibi ing low-
908
le el in lamma ion educe he p o ein agg ega ion and disease p og ession?
909
- Conside ing he ole o MERCS in ans e ing signals o mi ochond ia and modi ying
910
mi ochond ial memb anes, a e hey esponsible o he selec i e con en elease om
911
he apop o ic po es? Do MERCS di ec ly media e m DNA elease and p o-
912
in lamma o y signalling upon apop o ic machine y ac i a ion?
913
- Could a ge ing he non-canonical oles o BCL-2 p o eins in MERCS dynamics and
914
apop o ic signaling unlock g oundb eaking he apies o hal ing o e en e e sing
915
neu odegene a i e diseases like Pa kinson's and Alzheime 's?
916
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