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Dynamic control of mitochondria-associated membranes by kinases and phosphatases in health and disease

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Abstract

Membrane-contact sites are getting more and more credit for their indispensable role in maintenance of cell function and homeostasis. In the last decades, the ER–mitochondrial contact sites in particular received a lot of attention. While our knowledge of ER–mitochondrial contact sites increases steadily, the focus often lies on a static exploration of their functions. However, it is increasingly clear that these contact sites are very dynamic. In this review, we highlight the dynamic nature of ER–mitochondrial contact sites and the role of kinases and phosphatases therein with a focus on recent findings. Phosphorylation events allow for rapid integration of information on the protein level, impacting protein function, localization and interaction at ER–mitochondrial contact sites. To illustrate the importance of these events and to put them in a broader perspective, we connect them to pathologies like diabetes type II, Parkinson’s disease and cancer.

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References

  1. Abrahamian M, Kagda M, Ah-Fong AMV, Judelson HS (2017) Rethinking the evolution of eukaryotic metabolism: novel cellular partitioning of enzymes in stramenopiles links serine biosynthesis to glycolysis in mitochondria. BMC Evol Biol 17:241

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Prinz WA, Toulmay A, Balla T (2020) The functional universe of membrane contact sites. Nat Rev Mol Cell Biol 21:7–24

    Article  CAS  PubMed  Google Scholar 

  3. Sassano ML, van Vliet AR, Agostinis P (2017) Mitochondria-associated membranes as networking platforms and regulators of cancer cell fate. Front Oncol 7:174

    Article  PubMed  PubMed Central  Google Scholar 

  4. Vance JE (1990) Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265:7248–7256

    Article  CAS  PubMed  Google Scholar 

  5. Flis VV, Daum G (2013) Lipid transport between the endoplasmic reticulum and mitochondria. Cold Spring Harb Perspect Biol 5:a013235

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Marchi S, Bittremieux M, Missiroli S, Morganti C, Patergnani S, Sbano L, Rimessi A, Kerkhofs M, Parys JB, Bultynck G, Giorgi C, Pinton P (2017) Endoplasmic reticulum-mitochondria communication through Ca(2+) signaling: the importance of mitochondria-associated membranes (MAMs). Adv Exp Med Biol 997:49–67

    Article  CAS  PubMed  Google Scholar 

  7. van Vliet AR, Verfaillie T, Agostinis P (1843) New functions of mitochondria associated membranes in cellular signaling. Biochim Biophys Acta 2014:2253–2262

    Google Scholar 

  8. Eisenberg-Bord M, Shai N, Schuldiner M, Bohnert M (2016) A tether is a tether is a tether: tethering at membrane contact sites. Dev Cell 39:395–409

    Article  CAS  PubMed  Google Scholar 

  9. Szabadkai G, Bianchi K, Varnai P, De Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T, Rizzuto R (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175:901–911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Filadi R, Leal NS, Schreiner B, Rossi A, Dentoni G, Pinho CM, Wiehager B, Cieri D, Calì T, Pizzo P, Ankarcrona M (2018) TOM70 sustains cell bioenergetics by promoting IP3R3-mediated ER to mitochondria Ca(2+) transfer. Curr Biol 28:369-382.e366

    Article  CAS  PubMed  Google Scholar 

  11. Liu Y, Ma X, Fujioka H, Liu J, Chen S, Zhu X (2019) DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1. Proc Natl Acad Sci USA 116:25322–25328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Matsuzaki H, Fujimoto T, Tanaka M, Shirasawa S (2013) Tespa1 is a novel component of mitochondria-associated endoplasmic reticulum membranes and affects mitochondrial calcium flux. Biochem Biophys Res Commun 433:322–326

    Article  CAS  PubMed  Google Scholar 

  13. Thoudam T, Ha CM, Leem J, Chanda D, Park JS, Kim HJ, Jeon JH, Choi YK, Liangpunsakul S, Huh YH, Kwon TH, Park KG, Harris RA, Park KS, Rhee HW, Lee IK (2019) PDK4 augments ER-mitochondria contact to dampen skeletal muscle insulin signaling during obesity. Diabetes 68:571–586

    Article  CAS  PubMed  Google Scholar 

  14. D’Eletto M, Rossin F, Occhigrossi L, Farrace MG, Faccenda D, Desai R, Marchi S, Refolo G, Falasca L, Antonioli M, Ciccosanti F, Fimia GM, Pinton P, Campanella M, Piacentini M (2018) Transglutaminase type 2 regulates ER-mitochondria contact sites by interacting with GRP75. Cell Rep 25:3573-3581.e3574

    Article  CAS  PubMed  Google Scholar 

  15. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610

    Article  PubMed  CAS  Google Scholar 

  16. Naon D, Zaninello M, Giacomello M, Varanita T, Grespi F, Lakshminaranayan S, Serafini A, Semenzato M, Herkenne S, Hernandez-Alvarez MI, Zorzano A, De Stefani D, Dorn GW 2nd, Scorrano L (2016) Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci USA 113:11249–11254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P (2015) Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc Natl Acad Sci USA 112:E2174-2181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Leal NS, Schreiner B, Pinho CM, Filadi R, Wiehager B, Karlstrom H, Pizzo P, Ankarcrona M (2016) Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid beta-peptide production. J Cell Mol Med 20:1686–1695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Iwasawa R, Mahul-Mellier AL, Datler C, Pazarentzos E, Grimm S (2011) Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. EMBO J 30:556–568

    Article  CAS  PubMed  Google Scholar 

  20. Namba T (2019) BAP31 regulates mitochondrial function via interaction with Tom40 within ER-mitochondria contact sites. Sci Adv 5:eaaw1386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. De Vos KJ, Mórotz GM, Stoica R, Tudor EL, Lau KF, Ackerley S, Warley A, Shaw CE, Miller CC (2012) VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet 21:1299–1311

    Article  PubMed  CAS  Google Scholar 

  22. Stoica R, De Vos KJ, Paillusson S, Mueller S, Sancho RM, Lau KF, Vizcay-Barrena G, Lin WL, Xu YF, Lewis J, Dickson DW, Petrucelli L, Mitchell JC, Shaw CE, Miller CC (2014) ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun 5:3996

    Article  CAS  PubMed  Google Scholar 

  23. Guillén-Samander A, Leonzino M, Hanna MG, Tang N, Shen H, De Camilli P (2021) VPS13D bridges the ER to mitochondria and peroxisomes via miro. J Cell Biol 220:e202010004

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Lee S, Lee KS, Huh S, Liu S, Lee DY, Hong SH, Yu K, Lu B (2016) Polo kinase phosphorylates miro to control ER-mitochondria contact sites and mitochondrial Ca(2+) homeostasis in neural stem cell development. Dev Cell 37:174–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Saotome M, Safiulina D, Szabadkai G, Das S, Fransson A, Aspenstrom P, Rizzuto R, Hajnóczky G (2008) Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci USA 105:20728–20733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hung V, Lam SS, Udeshi ND, Svinkina T, Guzman G, Mootha VK, Carr SA, Ting AY (2017) Proteomic mapping of cytosol-facing outer mitochondrial and ER membranes in living human cells by proximity biotinylation. Elife 6:e24463

    Article  PubMed  PubMed Central  Google Scholar 

  27. Simmen T, Aslan JE, Blagoveshchenskaya AD, Thomas L, Wan L, Xiang Y, Feliciangeli SF, Hung CH, Crump CM, Thomas G (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24:717–729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Verfaillie T, Rubio N, Garg AD, Bultynck G, Rizzuto R, Decuypere JP, Piette J, Linehan C, Gupta S, Samali A, Agostinis P (2012) PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ 19:1880–1891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Doghman-Bouguerra M, Granatiero V, Sbiera S, Sbiera I, Lacas-Gervais S, Brau F, Fassnacht M, Rizzuto R, Lalli E (2016) FATE1 antagonizes calcium- and drug-induced apoptosis by uncoupling ER and mitochondria. EMBO Rep 17:1264–1280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Boucher J, Kleinridders A, Kahn CR (2014) Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 6:a009191

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, Hu FB, Kahn CR, Raz I, Shulman GI, Simonson DC, Testa MA, Weiss R (2015) Type 2 diabetes mellitus. Nat Rev Dis Primers 1:15019

    Article  PubMed  Google Scholar 

  32. Tubbs E, Theurey P, Vial G, Bendridi N, Bravard A, Chauvin MA, Ji-Cao J, Zoulim F, Bartosch B, Ovize M, Vidal H, Rieusset J (2014) Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance. Diabetes 63:3279–3294

    Article  CAS  PubMed  Google Scholar 

  33. Tubbs E, Chanon S, Robert M, Bendridi N, Bidaux G, Chauvin MA, Ji-Cao J, Durand C, Gauvrit-Ramette D, Vidal H, Lefai E, Rieusset J (2018) Disruption of mitochondria-associated endoplasmic reticulum membrane (MAM) integrity contributes to muscle insulin resistance in mice and humans. Diabetes 67:636–650

    Article  CAS  PubMed  Google Scholar 

  34. Sebastián D, Hernández-Alvarez MI, Segalés J, Sorianello E, Muñoz JP, Sala D, Waget A, Liesa M, Paz JC, Gopalacharyulu P, Orešič M, Pich S, Burcelin R, Palacín M, Zorzano A (2012) Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci U S A 109:5523–5528

    Article  PubMed  PubMed Central  Google Scholar 

  35. Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest 112:197–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N, Hall MN (2013) Feature article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology. Proc Natl Acad Sci USA 110:12526–12534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Miyamoto S, Murphy AN, Brown JH (2008) Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ 15:521–529

    Article  CAS  PubMed  Google Scholar 

  38. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, Hay N (2004) Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 16:819–830

    Article  CAS  PubMed  Google Scholar 

  39. Rabbani N, Thornalley PJ (2019) Hexokinase-2 glycolytic overload in diabetes and ischemia-reperfusion injury. Trends Endocrinol Metab 30:419–431

    Article  CAS  PubMed  Google Scholar 

  40. Pastorino JG, Hoek JB, Shulga N (2005) Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 65:10545–10554

    Article  CAS  PubMed  Google Scholar 

  41. Hermida MA, Dinesh Kumar J, Leslie NR (2017) GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv Biol Regul 65:5–15

    Article  CAS  PubMed  Google Scholar 

  42. Arruda AP, Pers BM, Parlakgül G, Güney E, Inouye K, Hotamisligil GS (2014) Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med 20:1427–1435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Theurey P, Tubbs E, Vial G, Jacquemetton J, Bendridi N, Chauvin MA, Alam MR, Le Romancer M, Vidal H, Rieusset J (2016) Mitochondria-associated endoplasmic reticulum membranes allow adaptation of mitochondrial metabolism to glucose availability in the liver. J Mol Cell Biol 8:129–143

    Article  CAS  PubMed  Google Scholar 

  44. Giorgi C, Ito K, Lin HK, Santangelo C, Wieckowski MR, Lebiedzinska M, Bononi A, Bonora M, Duszynski J, Bernardi R, Rizzuto R, Tacchetti C, Pinton P, Pandolfi PP (2010) PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330:1247–1251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bassot A, Chauvin MA, Bendridi N, Ji-Cao J, Vial G, Monnier L, Bartosch B, Alves A, Cottet-Rousselle C, Gouriou Y, Rieusset J, Morio B (2019) Regulation of mitochondria-associated membranes (MAMs) by NO/sGC/PKG participates in the control of hepatic insulin response. Cells 8:1319

    Article  CAS  PubMed Central  Google Scholar 

  46. Tonks KT, Ng Y, Miller S, Coster AC, Samocha-Bonet D, Iseli TJ, Xu A, Patrick E, Yang JY, Junutula JR, Modrusan Z, Kolumam G, Stöckli J, Chisholm DJ, James DE, Greenfield JR (2013) Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects. Diabetologia 56:875–885

    Article  CAS  PubMed  Google Scholar 

  47. Shao J, Yamashita H, Qiao L, Friedman JE (2000) Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. J Endocrinol 167:107–115

    Article  CAS  PubMed  Google Scholar 

  48. Henriksen EJ, Dokken BB (2006) Role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. Curr Drug Targets 7:1435–1441

    Article  CAS  PubMed  Google Scholar 

  49. Hu Y, Chen H, Zhang L, Lin X, Li X, Zhuang H, Fan H, Meng T, He Z, Huang H, Gong Q, Zhu D, Xu Y, He P, Li L, Feng D (2021) The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses. Autophagy 17:1142–1156

    Article  CAS  PubMed  Google Scholar 

  50. Vara-Perez M, Felipe-Abrio B, Agostinis P (2019) Mitophagy in cancer: a tale of adaptation. Cells 8:493

    Article  CAS  PubMed Central  Google Scholar 

  51. Truban D, Hou X, Caulfield TR, Fiesel FC, Springer W (2017) PINK1, Parkin, and mitochondrial quality control: what can we learn about Parkinson’s disease pathobiology? J Parkinsons Dis 7:13–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gelmetti V, De Rosa P, Torosantucci L, Marini ES, Romagnoli A, Di Rienzo M, Arena G, Vignone D, Fimia GM, Valente EM (2017) PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation. Autophagy 13:654–669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, Oomori H, Noda T, Haraguchi T, Hiraoka Y, Amano A, Yoshimori T (2013) Autophagosomes form at ER-mitochondria contact sites. Nature 495:389–393

    Article  CAS  PubMed  Google Scholar 

  54. Wu W, Tian W, Hu Z, Chen G, Huang L, Li W, Zhang X, Xue P, Zhou C, Liu L, Zhu Y, Li L, Zhang L, Sui S, Zhao B, Feng D (2014) ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep 15:566–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wu W, Li W, Chen H, Jiang L, Zhu R, Feng D (2016) FUNDC1 is a novel mitochondrial-associated-membrane (MAM) protein required for hypoxia-induced mitochondrial fission and mitophagy. Autophagy 12:1675–1676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Guardia-Laguarta C, Liu Y, Lauritzen KH, Erdjument-Bromage H, Martin B, Swayne TC, Jiang X, Przedborski S (2019) PINK1 content in mitochondria is regulated by ER-associated degradation. J Neurosci 39:7074–7085

    Article  PubMed  PubMed Central  Google Scholar 

  57. Yamano K, Youle RJ (2013) PINK1 is degraded through the N-end rule pathway. Autophagy 9:1758–1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Barazzuol L, Giamogante F, Brini M, Calì T (2020) PINK1/Parkin mediated mitophagy, Ca(2+) signalling, and ER-mitochondria contacts in Parkinson’s disease. Int J Mol Sci 21:1772

    Article  CAS  PubMed Central  Google Scholar 

  59. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG, Gourlay R, Burchell L, Walden H, Macartney TJ, Deak M, Knebel A, Alessi DR, Muqit MM (2012) PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol 2:120080

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Okatsu K, Koyano F, Kimura M, Kosako H, Saeki Y, Tanaka K, Matsuda N (2015) Phosphorylated ubiquitin chain is the genuine Parkin receptor. J Cell Biol 209:111–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, Alessi DR, Knebel A, Trost M, Muqit MM (2014) Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J 460:127–139

    Article  CAS  PubMed  Google Scholar 

  63. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, Youle RJ (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen Y, Dorn GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191:1367–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12:119–131

    Article  CAS  PubMed  Google Scholar 

  67. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, LaVoie MJ, Schwarz TL (2011) PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147:893–906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. McLelland GL, Goiran T, Yi W, Dorval G, Chen CX, Lauinger ND, Krahn AI, Valimehr S, Rakovic A, Rouiller I, Durcan TM, Trempe JF, Fon EA (2018) Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy. Elife 7:e32866

    Article  PubMed  PubMed Central  Google Scholar 

  69. Han H, Tan J, Wang R, Wan H, He Y, Yan X, Guo J, Gao Q, Li J, Shang S, Chen F, Tian R, Liu W, Liao L, Tang B, Zhang Z (2020) PINK1 phosphorylates Drp 1(S616) to regulate mitophagy-independent mitochondrial dynamics. EMBO Rep 21:e48686

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Pryde KR, Smith HL, Chau KY, Schapira AH (2016) PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy. J Cell Biol 213:163–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sugo M, Kimura H, Arasaki K, Amemiya T, Hirota N, Dohmae N, Imai Y, Inoshita T, Shiba-Fukushima K, Hattori N, Cheng J, Fujimoto T, Wakana Y, Inoue H, Tagaya M (2018) Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy. EMBO J 37:e98899

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Lavie J, Serrat R, Bellance N, Courtand G, Dupuy JW, Tesson C, Coupry I, Brice A, Lacombe D, Durr A, Stevanin G, Darios F, Rossignol R, Goizet C, Bénard G (2017) Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation. Hum Mol Genet 26:674–685

    CAS  PubMed  Google Scholar 

  73. Yu R, Liu T, Ning C, Tan F, Jin SB, Lendahl U, Zhao J, Nistér M (2019) The phosphorylation status of Ser-637 in dynamin-related protein 1 (Drp1) does not determine Drp1 recruitment to mitochondria. J Biol Chem 294:17262–17277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Park YS, Choi SE, Koh HC (2018) PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction. Toxicol Lett 284:120–128

    Article  CAS  PubMed  Google Scholar 

  75. Sekine S, Kanamaru Y, Koike M, Nishihara A, Okada M, Kinoshita H, Kamiyama M, Maruyama J, Uchiyama Y, Ishihara N, Takeda K, Ichijo H (2012) Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. J Biol Chem 287:34635–34645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Soutar MPM, Kempthorne L, Miyakawa S, Annuario E, Melandri D, Harley J, O’Sullivan GA, Wray S, Hancock DC, Cookson MR, Downward J, Carlton M, Plun-Favreau H (2018) AKT signalling selectively regulates PINK1 mitophagy in SHSY5Y cells and human iPSC-derived neurons. Sci Rep 8:8855

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Wang L, Cho YL, Tang Y, Wang J, Park JE, Wu Y, Wang C, Tong Y, Chawla R, Zhang J, Shi Y, Deng S, Lu G, Tan HW, Pawijit P, Lim GG, Chan HY, Fang L, Yu H, Liou YC, Karthik M, Bay BH, Lim KL, Sze SK, Yap CT, Shen HM (2018) PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1-Parkin-mediated mitophagy. Cell Res 28:787–802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Li G, Yang J, Yang C, Zhu M, Jin Y, McNutt MA, Yin Y (2018) PTENα regulates mitophagy and maintains mitochondrial quality control. Autophagy 14:1742–1760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dernie F (2020) Mitophagy in Parkinson’s disease: from pathogenesis to treatment target. Neurochem Int 138:104756

    Article  CAS  PubMed  Google Scholar 

  80. Grayson M (2016) Parkinson’s disease. Nature 538:S1

    Article  CAS  PubMed  Google Scholar 

  81. Loncke J, Kaasik A, Bezprozvanny I, Parys JB, Kerkhofs M, Bultynck G (2021) Balancing ER-mitochondrial Ca(2+) fluxes in health and disease. Trends Cell Biol 31:598–612

    Article  CAS  PubMed  Google Scholar 

  82. Aguirre JD, Dunkerley KM, Lam R, Rusal M, Shaw GS (2018) Impact of altered phosphorylation on loss of function of juvenile Parkinsonism-associated genetic variants of the E3 ligase parkin. J Biol Chem 293:6337–6348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rakovic A, Grünewald A, Kottwitz J, Brüggemann N, Pramstaller PP, Lohmann K, Klein C (2011) Mutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts. PLoS One 6:e16746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gautier CA, Erpapazoglou Z, Mouton-Liger F, Muriel MP, Cormier F, Bigou S, Duffaure S, Girard M, Foret B, Iannielli A, Broccoli V, Dalle C, Bohl D, Michel PP, Corvol JC, Brice A, Corti O (2016) The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations. Hum Mol Genet 25:2972–2984

    CAS  PubMed  Google Scholar 

  85. Parrado-Fernández C, Schneider B, Ankarcrona M, Conti MM, Cookson MR, Kivipelto M, Cedazo-Mínguez Á, Sandebring-Matton A (2018) Reduction of PINK1 or DJ-1 impair mitochondrial motility in neurites and alter ER-mitochondria contacts. J Cell Mol Med 22:5439–5449

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Calì T, Ottolini D, Negro A, Brini M (2013) Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca(2+) transfer to sustain cell bioenergetics. Biochim Biophys Acta 1832:495–508

    Article  PubMed  CAS  Google Scholar 

  87. Basso V, Marchesan E, Peggion C, Chakraborty J, von Stockum S, Giacomello M, Ottolini D, Debattisti V, Caicci F, Tasca E, Pegoraro V, Angelini C, Antonini A, Bertoli A, Brini M, Ziviani E (2018) Regulation of ER-mitochondria contacts by Parkin via Mfn2. Pharmacol Res 138:43–56

    Article  CAS  PubMed  Google Scholar 

  88. Singh F, Ganley IG (2021) Parkinson’s disease and mitophagy: an emerging role for LRRK2. Biochem Soc Trans 49:551–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wauters F, Cornelissen T, Imberechts D, Martin S, Koentjoro B, Sue C, Vangheluwe P, Vandenberghe W (2020) LRRK2 mutations impair depolarization-induced mitophagy through inhibition of mitochondrial accumulation of RAB10. Autophagy 16:203–222

    Article  CAS  PubMed  Google Scholar 

  90. Alessi DR, Sammler E (2018) LRRK2 kinase in Parkinson’s disease. Science 360:36–37

    Article  CAS  PubMed  Google Scholar 

  91. Korecka JA, Thomas R, Christensen DP, Hinrich AJ, Ferrari EJ, Levy SA, Hastings ML, Hallett PJ, Isacson O (2019) Mitochondrial clearance and maturation of autophagosomes are compromised in LRRK2 G2019S familial Parkinson’s disease patient fibroblasts. Hum Mol Genet 28:3232–3243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Toyofuku T, Okamoto Y, Ishikawa T, Sasawatari S, Kumanogoh A (2020) LRRK2 regulates endoplasmic reticulum-mitochondrial tethering through the PERK-mediated ubiquitination pathway. EMBO J 39:e100875

    Article  CAS  PubMed  Google Scholar 

  93. Lee JH, Han JH, Kim H, Park SM, Joe EH, Jou I (2019) Parkinson’s disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes. Acta Neuropathol Commun 7:68

    Article  PubMed  PubMed Central  Google Scholar 

  94. Hsieh CH, Shaltouki A, Gonzalez AE, da Cruz AB, Burbulla LF, St Lawrence E, Schüle B, Krainc D, Palmer TD, Wang X (2016) Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell 19:709–724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hao LY, Giasson BI, Bonini NM (2010) DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function. Proc Natl Acad Sci USA 107:9747–9752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Greene LA, Levy O, Malagelada C (2011) Akt as a victim, villain and potential hero in Parkinson’s disease pathophysiology and treatment. Cell Mol Neurobiol 31:969–978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Aleyasin H, Rousseaux MW, Marcogliese PC, Hewitt SJ, Irrcher I, Joselin AP, Parsanejad M, Kim RH, Rizzu P, Callaghan SM, Slack RS, Mak TW, Park DS (2010) DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway. Proc Natl Acad Sci USA 107:3186–3191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Huang Y, Sun L, Zhu S, Xu L, Liu S, Yuan C, Guo Y, Wang X (2020) Neuroprotection against Parkinson’s disease through the activation of Akt/GSK3β signaling pathway by Tovophyllin A. Front Neurosci 14:723

    Article  PubMed  PubMed Central  Google Scholar 

  99. Bootman MD, Bultynck G (2020) Fundamentals of cellular calcium signaling: a primer. Cold Spring Harb Perspect Biol 12:a038802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Loncke J, Kerkhofs M, Kaasik A, Bezprozvanny I, Bultynck G (2020) Recent advances in understanding IP3R function with focus on ER-mitochondrial Ca2+ transfers. Curr Opin Physiol 17:80–88

    Article  Google Scholar 

  101. Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13:566–578

    Article  CAS  PubMed  Google Scholar 

  102. Kerkhofs M, Giorgi C, Marchi S, Seitaj B, Parys JB, Pinton P, Bultynck G, Bittremieux M (2017) Alterations in Ca(2+) signalling via ER-mitochondria contact site remodelling in cancer. Adv Exp Med Biol 997:225–254

    Article  CAS  PubMed  Google Scholar 

  103. Bootman MD, Chehab T, Bultynck G, Parys JB, Rietdorf K (2018) The regulation of autophagy by calcium signals: do we have a consensus? Cell Calcium 70:32–46

    Article  CAS  PubMed  Google Scholar 

  104. Ivanova H, Kerkhofs M, La Rovere RM, Bultynck G (2017) Endoplasmic reticulum-mitochondrial Ca2+ fluxes underlying cancer cell survival. Front Oncol 7:70

    Article  PubMed  PubMed Central  Google Scholar 

  105. Prole DL, Taylor CW (2016) Inositol 1,4,5-trisphosphate receptors and their protein partners as signalling hubs. J Physiol 594:2849–2866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Parys JB, Vervliet T (2020) New insights in the IP(3) receptor and its regulation. Adv Exp Med Biol 1131:243–270

    Article  CAS  PubMed  Google Scholar 

  107. Vanderheyden V, Devogelaere B, Missiaen L, De Smedt H, Bultynck G, Parys JB (2009) Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylation. Biochim Biophys Acta 1793:959–970

    Article  CAS  PubMed  Google Scholar 

  108. Akl H, Bultynck G (1835) Altered Ca(2+) signaling in cancer cells: proto-oncogenes and tumor suppressors targeting IP3 receptors. Biochim Biophys Acta 2013:180–193

    Google Scholar 

  109. Bittremieux M, Parys JB, Pinton P, Bultynck G (1863) ER functions of oncogenes and tumor suppressors: Modulators of intracellular Ca(2+) signaling. Biochim Biophys Acta 2016:1364–1378

    Google Scholar 

  110. Monteith GR, Prevarskaya N, Roberts-Thomson SJ (2017) The calcium-cancer signalling nexus. Nat Rev Cancer 17:367–380

    Article  CAS  PubMed  Google Scholar 

  111. Danese A, Leo S, Rimessi A, Wieckowski MR, Fiorica F, Giorgi C, Pinton P (2021) Cell death as a result of calcium signaling modulation: A cancer-centric prospective. Biochim Biophys Acta Mol Cell Res 1868:119061

    Article  CAS  PubMed  Google Scholar 

  112. Marchi S, Marinello M, Bononi A, Bonora M, Giorgi C, Rimessi A, Pinton P (2012) Selective modulation of subtype III IP3R by Akt regulates ER Ca2+ release and apoptosis. Cell Death Dis 3:e304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bononi A, Bonora M, Marchi S, Missiroli S, Poletti F, Giorgi C, Pandolfi PP, Pinton P (2013) Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner. Cell Death Differ 20(12):1631–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R (2016) Landscape of phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid tumors. JAMA Oncol 2:1565–1573

    Article  PubMed  Google Scholar 

  115. Lee YR, Chen M, Pandolfi PP (2018) The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol 19:547–562

    Article  CAS  PubMed  Google Scholar 

  116. Kuchay S, Giorgi C, Simoneschi D, Pagan J, Missiroli S, Saraf A, Florens L, Washburn MP, Collazo-Lorduy A, Castillo-Martin M, Cordon-Cardo C, Sebti SM, Pinton P, Pagano M (2017) PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth. Nature 546:554–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Carreras-Sureda A, Jaña F, Urra H, Durand S, Mortenson DE, Sagredo A, Bustos G, Hazari Y, Ramos-Fernández E, Sassano ML, Pihán P, van Vliet AR, González-Quiroz M, Torres AK, Tapia-Rojas C, Kerkhofs M, Vicente R, Kaufman RJ, Inestrosa NC, Gonzalez-Billault C, Wiseman RL, Agostinis P, Bultynck G, Court FA, Kroemer G, Cárdenas JC, Hetz C (2019) Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics. Nat Cell Biol 21:755–767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Betzenhauser MJ, Yule DI (2010) Regulation of inositol 1,4,5-trisphosphate receptors by phosphorylation and adenine nucleotides. Curr Top Membr 66:273–298

    Article  CAS  PubMed  Google Scholar 

  119. Soulsby MD, Wojcikiewicz RJ (2007) Calcium mobilization via type III inositol 1,4,5-trisphosphate receptors is not altered by PKA-mediated phosphorylation of serines 916, 934, and 1832. Cell Calcium 42:261–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bui M, Gilady SY, Fitzsimmons RE, Benson MD, Lynes EM, Gesson K, Alto NM, Strack S, Scott JD, Simmen T (2010) Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties. J Biol Chem 285:31590–31602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chang MJ, Zhong F, Lavik AR, Parys JB, Berridge MJ, Distelhorst CW (2014) Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival. Proc Natl Acad Sci USA 111:1186–1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gomez L, Thiebaut PA, Paillard M, Ducreux S, Abrial M, Crola Da Silva C, Durand A, Alam MR, Van Coppenolle F, Sheu SS, Ovize M (2016) The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury. Cell Death Differ 23:313–322

    Article  CAS  PubMed  Google Scholar 

  123. Ciscato F, Filadi R, Masgras I, Pizzi M, Marin O, Damiano N, Pizzo P, Gori A, Frezzato F, Chiara F, Trentin L, Bernardi P, Rasola A (2020) Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca(2+) -dependent death of cancer cells. EMBO Rep 21:e49117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kerkhofs M, La Rovere R, Welkenhuysen K, Janssens A, Vandenberghe P, Madesh M, Parys JB, Bultynck G (2021) BIRD-2, a BH4-domain-targeting peptide of Bcl-2, provokes Bax/Bak-independent cell death in B-cell cancers through mitochondrial Ca(2+)-dependent mPTP opening. Cell Calcium 94:102333

    Article  CAS  PubMed  Google Scholar 

  125. Rong YP, Bultynck G, Aromolaran AS, Zhong F, Parys JB, De Smedt H, Mignery GA, Roderick HL, Bootman MD, Distelhorst CW (2009) The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor. Proc Natl Acad Sci USA 106:14397–14402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zhong F, Harr MW, Bultynck G, Monaco G, Parys JB, De Smedt H, Rong YP, Molitoris JK, Lam M, Ryder C, Matsuyama S, Distelhorst CW (2011) Induction of Ca(2)+-driven apoptosis in chronic lymphocytic leukemia cells by peptide-mediated disruption of Bcl-2-IP3 receptor interaction. Blood 117:2924–2934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Bittremieux M, La Rovere RM, Akl H, Martines C, Welkenhuyzen K, Dubron K, Baes M, Janssens A, Vandenberghe P, Laurenti L, Rietdorf K, Morciano G, Pinton P, Mikoshiba K, Bootman MD, Efremov DG, De Smedt H, Parys JB, Bultynck G (2019) Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2. Cell Death Differ 26:531–547

    Article  CAS  PubMed  Google Scholar 

  128. de Ridder I, Kerkhofs M, Veettil SP, Dehaen W, Bultynck G (2021) Cancer cell death strategies by targeting Bcl-2’s BH4 domain. Biochim Biophys Acta Mol Cell Res 1868:118983

    Article  PubMed  CAS  Google Scholar 

  129. Kerkhofs M, Bittremieux M, Morciano G, Giorgi C, Pinton P, Parys JB, Bultynck G (2018) Emerging molecular mechanisms in chemotherapy: Ca(2+) signaling at the mitochondria-associated endoplasmic reticulum membranes. Cell Death Dis 9:334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Funding

Research in the authors’ laboratories was supported by research grants from the Research Foundation—Flanders (FWO) (G.0A34.16N, G.0901.18N, and G.0818.21N to G.B.. M.K. obtained a doctoral fellowship from the FWO.

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  1. Monika Pichla and Flore Sneyers have contributed equally to the manuscript.

Authors and Affiliations

  1. Lab for Molecular and Cellular Signalling, Department for Cellular and Molecular Medicine, Leuven Kanker Instituut, KU Leuven, Leuven, Belgium

    Flore Sneyers, Geert Bultynck & Martijn Kerkhofs

  2. Department of Analytical Biochemistry, Institute of Food Technology and Nutrition, College of Natural Sciences, Rzeszow University, Rzeszow, Poland

    Monika Pichla

  3. Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland

    Kinga B. Stopa

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  1. Monika Pichla
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  2. Flore Sneyers
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MK conceptualized the manuscript; MP, FS, KBS and MK drafted the manuscript and made the figures. GB corrected the manuscript and gave helpful feedback.

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Correspondence to Martijn Kerkhofs.

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Pichla, M., Sneyers, F., Stopa, K.B. et al. Dynamic control of mitochondria-associated membranes by kinases and phosphatases in health and disease. Cell. Mol. Life Sci. 78, 6541–6556 (2021). https://doi.org/10.1007/s00018-021-03920-9

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