Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons

Grossmann, Dajana; Malburg, Nina; Glaß, Hannes; Weeren, Veronika; Sondermann, Verena; Pfeiffer, Julia F.; Petters, Janine; Lukas, Jan; Seibler, Philip; Klein, Christine; GRÜNEWALD, Anne; Hermann, Andreas

doi:10.1002/mds.29525

Article (Scientific journals)

Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons

Grossmann, Dajana; Malburg, Nina; Glaß, Hannes et al.

2023 • In Movement disorders : official journal of the Movement Disorder Society

Peer reviewed

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https://hdl.handle.net/10993/55633

DOI
10.1002/mds.29525

PubMed
37449534

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Abstract :

[en] Background: It is generally believed that the pathogenesis of PINK1/parkin-related Parkinson's disease (PD) is due to a disturbance in mitochondrial quality control. However, recent studies have found that PINK1 and Parkin play a significant role in mitochondrial calcium homeostasis and are involved in the regulation of mitochondria-endoplasmic reticulum contact sites (MERCSs). Objective: The aim of our study was to perform an in-depth analysis of the role of MERCSs and impaired calcium homeostasis in PINK1/Parkin-linked PD.<h4>Methods</h4>In our study, we used induced pluripotent stem cell-derived dopaminergic neurons from patients with PD with loss-of-function mutations in PINK1 or PRKN. We employed a split-GFP-based contact site sensor in combination with the calcium-sensitive dye Rhod-2 AM and applied Airyscan live-cell super-resolution microscopy to determine how MERCSs are involved in the regulation of mitochondrial calcium homeostasis. Results: Our results showed that thapsigargin-induced calcium stress leads to an increase of the abundance of narrow MERCSs in wild-type neurons. Intriguingly, calcium levels at the MERCSs remained stable, whereas the increased net calcium influx resulted in elevated mitochondrial calcium levels. However, PINK1-PD or PRKN-PD neurons showed an increased abundance of MERCSs at baseline, accompanied by an inability to further increase MERCSs upon thapsigargin-induced calcium stress. Consequently, calcium distribution at MERCSs and within mitochondria was disrupted. Conclusions: Our results demonstrated how the endoplasmic reticulum and mitochondria work together to cope with calcium stress in wild-type neurons. In addition, our results suggests that PRKN deficiency affects the dynamics and composition of MERCSs differently from PINK1 deficiency, resulting in differentially affected calcium homeostasis. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Grossmann, Dajana

Malburg, Nina

Glaß, Hannes

Weeren, Veronika

Sondermann, Verena

Pfeiffer, Julia F.

Petters, Janine

Lukas, Jan

Seibler, Philip

Klein, Christine

GRÜNEWALD, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology

Hermann, Andreas

External co-authors :

yes

Language :

English

Title :

Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons

Publication date :

2023

Journal title :

Movement disorders : official journal of the Movement Disorder Society

ISSN :

0885-3185

Peer reviewed :

Peer reviewed

Additional URL :

https://doi.org/10.1002/mds.29525

FnR Project :

FNR9631103 - Modelling Idiopathic Parkinson'S Disease-associated Somatic Variation In Dopaminergic Neurons, 2015 (01/01/2016-31/12/2022) - Anne Grünewald

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Bibliography

Grünewald A, Kumar KR, Sue CM. New insights into the complex role of mitochondria in Parkinson's disease. Prog Neurobiol [Internet] 2019;177:73–93. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0301008218300650
Rakovic A, Grünewald A, Kottwitz J, Brüggemann N, Pramstaller PP, Lohmann K, et al. Mutations in PINK1 and parkin impair ubiquitination of Mitofusins in human fibroblasts. PLoS One [Internet] 2011;6(3):e16746. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21408142
Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet [Internet] 2007;16:R183–R194. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17911161
Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature [Internet] 1998;392(6676):605–608. Available from: http://www.nature.com/articles/33416
Lücking CB, Dürr A, Bonifati V, Vaughan J, De Michele G, Gasser T, et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med [Internet] 2000;342(21):1560–1567. Available from:. https://doi.org/10.1056/NEJM200005253422103
Valente EM, Abou-Sleiman PM, Caputo V, Muqit MMK, Harvey K, Gispert S, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science [Internet] 2004;304(5674):1158–1160. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15087508
Narendra D, Tanaka A, Suen D-F, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol [Internet] 2008;183(5):795–803. Available from: https://rupress.org/jcb/article/183/5/795/35265/Parkin-is-recruited-selectively-to-impaired
Valadas JS, Esposito G, Vandekerkhove D, Miskiewicz K, Deaulmerie L, Raitano S, et al. ER lipid defects in Neuropeptidergic neurons impair sleep patterns in Parkinson's disease. Neuron [Internet] 2018;98(6):1155–1169.e6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29887339
Cieri D, Vicario M, Giacomello M, Vallese F, Filadi R, Wagner T, et al. SPLICS: a split green fluorescent protein-based contact site sensor for narrow and wide heterotypic organelle juxtaposition. Cell Death Differ [Internet] 2018;25(6):1131–1145. Available from: http://www.nature.com/articles/s41418-017-0033-z
Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, et al. Autophagosomes form at ER-mitochondria contact sites. Nature [Internet] 2013;495(7441):389–393. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23455425
McLelland G-L, Goiran T, Yi W, Dorval G, Chen CX, Lauinger ND, et al. Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy. Elife [Internet] 2018;7:e32866. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29676259
Basso V, Marchesan E, Peggion C, Chakraborty J, von Stockum S, Giacomello M, et al. Regulation of ER-mitochondria contacts by parkin via Mfn2. Pharmacol Res [Internet] 2018;138:43–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30219582
Sun Y, Vashisht AA, Tchieu J, Wohlschlegel JA, Dreier L. Voltage-dependent anion channels (VDACs) recruit parkin to defective mitochondria to promote mitochondrial autophagy. J Biol Chem [Internet] 2012 Nov 23;287(48):40652–40660. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23060438
Birsa N, Norkett R, Wauer T, Mevissen TET, Wu HC, Foltynie T, et al. Lysine 27 ubiquitination of the mitochondrial transport protein miro is dependent on serine 65 of the parkin ubiquitin ligase. J Biol Chem 2014;289(21):14569–14582.
Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, et al. PINK1 and parkin target miro for phosphorylation and degradation to arrest mitochondrial motility. Cell [Internet] 2011;147(4):893–906. Available from:. https://doi.org/10.1016/j.cell.2011.10.018
Giacomello M, Pellegrini L. The coming of age of the mitochondria-ER contact: a matter of thickness. Cell Death Differ 2016;23(9):1417–1427.
Szabadkai G, Bianchi K, Várnai P, De Stefani D, Wieckowski MR, Cavagna D, et al. Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol [Internet] 2006;175(6):901–911. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17178908
Csordás G, Renken C, Várnai P, Walter L, Weaver D, Buttle KF, et al. Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol [Internet] 2006;174(7):915–921. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16982799
Csordás G, Várnai P, Golenár T, Roy S, Purkins G, Schneider TG, et al. Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell [Internet] 2010;39(1):121–132. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20603080
Gherardi G, Monticelli H, Rizzuto R, Mammucari C. The mitochondrial Ca2+ uptake and the fine-tuning of aerobic metabolism. Front Physiol [Internet] 2020;11:554904. Available from: http://www.ncbi.nlm.nih.gov/pubmed/33117189
Marcu R, Wiczer BM, Neeley CK, Hawkins BJ. Mitochondrial matrix Ca2+ accumulation regulates cytosolic NAD+/NADH metabolism, protein acetylation, and sirtuin expression. Mol Cell Biol [Internet] 2014;34(15):2890–2902. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24865966
Celardo I, Costa AC, Lehmann S, Jones C, Wood N, Mencacci NE, et al. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease. Cell Death Dis [Internet] 2016;7(6):e2271. Available from: http://www.nature.com/articles/cddis2016173
Lee K-S, Huh S, Lee S, Wu Z, Kim A-K, Kang H-Y, et al. Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models. Proc Natl Acad Sci U S A [Internet] 2018;115(38):E8844–E8853. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30185553
Gautier CA, Erpapazoglou Z, Mouton-Liger F, Muriel MP, Cormier F, Bigou S, et al. The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations. Hum Mol Genet [Internet] 2016;25(14):2972–2984. Available from: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddw148
Calì T, Ottolini D, Negro A, Brini M. Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca(2+) transfer to sustain cell bioenergetics. Biochim Biophys Acta [Internet] 2013;1832(4):495–508. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23313576
Parrado-Fernández C, Schreiner B, Ankarcrona M, Conti MM, Cookson MR, Kivipelto M, et al. Reduction of PINK1 or DJ-1 impair mitochondrial motility in neurites and alter ER-mitochondria contacts. J Cell Mol Med [Internet] 2018;22(11):5439–5449. Available from: https://onlinelibrary.wiley.com/doi/10.1111/jcmm.13815
Grünewald A, Breedveld GJ, Lohmann-Hedrich K, Rohé CF, König IR, Hagenah J, et al. Biological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis. Neurogenetics [Internet] 2007;8(2):103–109. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17219214
Wasner K, Smajic S, Ghelfi J, Delcambre S, Prada-Medina CA, Knappe E, et al. Parkin deficiency impairs mitochondrial DNA dynamics and propagates inflammation. Mov Disord [Internet] 2022;37(7):1405–1415. Available from: http://www.ncbi.nlm.nih.gov/pubmed/35460111
Petters J, Völkner C, Krohn S, Murua Escobar H, Bullerdiek J, Reuner U, et al. Generation of two induced pluripotent stem cell lines from a female adult homozygous for the Wilson disease associated ATP7B variant p.H1069Q (AKOSi008-a) and a healthy control (AKOSi009-a). Stem Cell Res [Internet] 2020;49:102079.vailable from: http://www.ncbi.nlm.nih.gov/pubmed/33197697
Peter F, Trilck M, Rabenstein M, Rolfs A, Frech MJ. Dataset in support of the generation of Niemann-pick disease type C1 patient-specific iPS cell lines carrying the novel NPC1 mutation c.1180T>C or the prevalent c.3182T>C mutation – analysis of pluripotency and neuronal differentiation. Data Br [Internet] 2017;12:123–131. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28413817
Zanon A, Kalvakuri S, Rakovic A, Foco L, Guida M, Schwienbacher C, et al. SLP-2 interacts with parkin in mitochondria and prevents mitochondrial dysfunction in parkin-deficient human iPSC-derived neurons and drosophila. Hum Mol Genet [Internet] 2017;26(13):2412–2425. Available from: https://academic.oup.com/hmg/article/26/13/2412/3098491
Trilck-Winkler M, Borsche M, König IR, Balck A, Lenz I, Kasten M, et al. Parkin deficiency appears not to Be associated with cardiac damage in Parkinson's disease. Mov Disord [Internet] 2021;36(1):271–273. Available from: https://onlinelibrary.wiley.com/doi/10.1002/mds.28422
Baud A, Wessely F, Mazzacuva F, McCormick J, Camuzeaux S, Heywood WE, et al. Multiplex high-throughput targeted proteomic assay to identify induced pluripotent stem cells. Anal Chem [Internet] 2017;89(4):2440–2448. Available from: https://pubs.acs.org/doi/10.1021/acs.analchem.6b04368
Reinhardt P, Glatza M, Hemmer K, Tsytsyura Y, Thiel CS, Höing S, et al. Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling. PLoS One [Internet] 2013;8(3):e59252. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23533608
Berenguer-Escuder C, Grossmann D, Antony P, Arena G, Wasner K, Massart F, et al. Impaired mitochondrial-endoplasmic reticulum interaction and mitophagy in Miro1-mutant neurons in Parkinson's disease. Hum Mol Genet [Internet] 2020;29(8):1353–1364. Available from: https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddaa066/5816586
Moltedo O, Remondelli P, Amodio G. The mitochondria–endoplasmic reticulum contacts and their critical role in aging and age-associated diseases. Front Cell Dev Biol [Internet] 2019;7:172. Available from: https://www.frontiersin.org/article/10.3389/fcell.2019.00172/full
Kornmann B, Osman C, Walter P. The conserved GTPase Gem1 regulates endoplasmic reticulum-mitochondria connections. Proc Natl Acad Sci [Internet] 2011;108(34):14151–14156. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.1111314108
Lee S, Lee K-S, Huh S, Liu S, Lee D-Y, Hong SH, et al. Polo kinase phosphorylates Miro to control ER-mitochondria contact sites and mitochondrial Ca 2+ homeostasis in neural stem cell development. Dev Cell [Internet] 2016 Apr;37(2):174–189. Available from:. https://doi.org/10.1016/j.devcel.2016.03.023
Berenguer-Escuder C, Grossmann D, Massart F, Antony P, Burbulla LF, Glaab E, et al. Variants in Miro1 cause alterations of ER-mitochondria contact sites in fibroblasts from Parkinson's disease patients. J Clin Med [Internet] 2019;8(12):2226. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31888276
Nemani N, Carvalho E, Tomar D, Dong Z, Ketschek A, Breves SL, et al. MIRO-1 determines mitochondrial shape transition upon GPCR activation and Ca2+stress. Cell Rep 2018;23(4):1005–1019.
Hajnóczky G, Booth D, Csordás G, Debattisti V, Golenár T, Naghdi S, et al. Reliance of ER–mitochondrial calcium signaling on mitochondrial EF-hand Ca2+ binding proteins: Miros, MICUs, LETM1 and solute carriers. Curr Opin Cell Biol [Internet] 2014;29(1):133–141. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0955067414000738
Lytton J, Westlin M, Hanley MR. Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem [Internet] 1991;266(26):17067–17071. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1832668
Eiyama A, Okamoto K. PINK1/parkin-mediated mitophagy in mammalian cells. Curr Opin Cell Biol [Internet] 2015 Apr;33:95–101. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25697963
Barazzuol L, Giamogante F, Brini M, Calì T. PINK1/parkin mediated mitophagy, Ca2+ Signalling, and ER-mitochondria contacts in Parkinson's disease. Int J Mol Sci [Internet] 2020;21(5):1772. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32150829
Bravo R, Vicencio JM, Parra V, Troncoso R, Munoz JP, Bui M, et al. Increased ER–mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. J Cell Sci [Internet] 2011;124(13):2143–2152. Available from: https://journals.biologists.com/jcs/article/124/13/2143/31830/Increased-ER-mitochondrial-coupling-promotes
Saotome M, Safiulina D, Szabadkai G, Das S, Fransson A, Aspenstrom P, et al. Bidirectional Ca2+−dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci [Internet] 2008;105(52):20728–20733. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.0808953105
Niescier RF, Hong K, Park D, Min K-T. MCU interacts with Miro1 to modulate mitochondrial functions in neurons. J Neurosci [Internet] 2018;38(20):4666–4677. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29686046
Jackson JG, Robinson MB. Reciprocal regulation of mitochondrial dynamics and calcium signaling in astrocyte processes. J Neurosci [Internet] 2015;35(45):15199–15213. Available from: http://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.2049-15.2015
Treiman M, Caspersen C, Christensen SB. A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca(2+)-ATPases. Trends Pharmacol Sci [Internet] 1998;19(4):131–135. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9612087
Guardia-Laguarta C, Liu Y, Lauritzen KH, Erdjument-Bromage H, Martin B, Swayne TC, et al. PINK1 content in mitochondria is regulated by ER-associated degradation. J Neurosci [Internet] 2019;39(36):7074–7085. Available from: http://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.1691-18.2019
Trychta KA, Bäck S, Henderson MJ, Harvey BK. KDEL receptors are differentially regulated to maintain the ER proteome under calcium deficiency. Cell Rep [Internet] 2018;25(7):1829–1840.e6. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2211124718316449