@article{4efbb17c0bea4a31bacdc47be85f5738,
title = "PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions",
abstract = "Mitochondrial crista structure partitions vital cellular reactions and is precisely regulated by diverse cellular signals. Here, we show that, in Drosophila, mitochondrial cristae undergo dynamic remodeling among distinct subcellular regions and the Parkinson's disease (PD)-linked Ser/Thr kinase PINK1 participates in their regulation. Mitochondria increase crista junctions and numbers in selective subcellular areas, and this remodeling requires PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60/mitofilin, which stabilizes MIC60 oligomerization. Expression of MIC60 restores crista structure and ATP levels of PINK1-null flies and remarkably rescues their behavioral defects and dopaminergic neurodegeneration. In an extension to human relevance, we discover that the PINK1-MIC60 pathway is conserved in human neurons, and expression of several MIC60 coding variants in the mitochondrial targeting sequence found in PD patients in Drosophila impairs crista junction formation and causes locomotion deficits. These findings highlight the importance of maintenance and plasticity of crista junctions to cellular homeostasis in vivo. Tsai et al. discover that mitochondria increase crista junctions and numbers in selective subcellular areas in Drosophila. This structural remodeling requires Parkinson's-linked PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60, which stabilizes MIC60 oligomerization. MIC60 functions downstream of PINK1 to maintain mitochondrial functions and cellular survival.",
keywords = "Drosophila, MIC60, PINK1, Parkinson's, cristae, mitochondria, mitofilin, oligomerization, phosphorylation, variant",
author = "Tsai, {Pei I.} and Lin, {Chin Hsien} and Hsieh, {Chung Han} and Papakyrikos, {Amanda M.} and Kim, {Min Joo} and Valerio Napolioni and Carmen Schoor and Julien Couthouis and Wu, {Ruey Meei} and Wszolek, {Zbigniew K.} and Dominic Winter and Greicius, {Michael D.} and Ross, {Owen A.} and Xinnan Wang",
note = "Funding Information: We thank Drs. B. Lu, J. Chung, M. Guo, S.K. Park, H. Bellen, L. Pallanck, and T. Clandinin for reagents and J. Perrino and the Stanford Cell Science Imaging EM Facility (1S10RR026780-01; the National Center for Research Resources) for assistance with the EM work. This work was supported by the Department of Defense ( PR150380 , X.W.; W81XWH-17-1-0249 , O.A.R), the Alfred P. Sloan Foundation (X.W.), the Klingenstein Foundation (X.W.), the Shurl and Kay Curci Foundation (X.W.), the Marie Curie Career Integration Grant (D.W.), the Junior Group Leader Fellowship of the Bonfor-Program at the University Hospital Bonn (D.W.), the Graduate Research Fellowship Program of the National Science Foundation (A.P.), the Postdoctoral Research Abroad Program of the National Science Council, Taiwan (P.T.), the awards from Mayo Clinic Neuroscience Focused Research Team and Mayo Clinic Center for Regenerative Medicine (Z.K.W. and O.A.R.), the Michael J. Fox Foundation (O.A.R.), NIH/NINDS ( R01 NS078086 ; O.A.R.), the gifts from Carl Edward Bolch Jr. and Susan Bass Bolch (Z.K.W.), the Sol Goldman Charitable Trust (Z.K.W.), and Donald G. and Jodi P. Heeringa (Z.K.W.). Mayo Clinic Florida is supported by a Morris K. Udall PD Research Center of Excellence ( NINDS P50 no. NS072187 ). PPMI is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including Abbvie , Avid , Biogen , Bristol-Myers Squibb , Covance , GE Healthcare , Genentech , GlaxoSmithKline , Lilly , Lundbeck , Merck , Meso Scale Discovery , Pfizer , Piramal , Roche , Servier , and UCB . Funding Information: We thank Drs. B. Lu, J. Chung, M. Guo, S.K. Park, H. Bellen, L. Pallanck, and T. Clandinin for reagents and J. Perrino and the Stanford Cell Science Imaging EM Facility (1S10RR026780-01; the National Center for Research Resources) for assistance with the EM work. This work was supported by the Department of Defense (PR150380, X.W.; W81XWH-17-1-0249, O.A.R), the Alfred P. Sloan Foundation (X.W.), the Klingenstein Foundation (X.W.), the Shurl and Kay Curci Foundation (X.W.), the Marie Curie Career Integration Grant (D.W.), the Junior Group Leader Fellowship of the Bonfor-Program at the University Hospital Bonn (D.W.), the Graduate Research Fellowship Program of the National Science Foundation (A.P.), the Postdoctoral Research Abroad Program of the National Science Council, Taiwan (P.T.), the awards from Mayo Clinic Neuroscience Focused Research Team and Mayo Clinic Center for Regenerative Medicine (Z.K.W. and O.A.R.), the Michael J. Fox Foundation (O.A.R.), NIH/NINDS (R01 NS078086; O.A.R.), the gifts from Carl Edward Bolch Jr. and Susan Bass Bolch (Z.K.W.), the Sol Goldman Charitable Trust (Z.K.W.), and Donald G. and Jodi P. Heeringa (Z.K.W.). Mayo Clinic Florida is supported by a Morris K. Udall PD Research Center of Excellence (NINDS P50 no. NS072187). PPMI is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including Abbvie, Avid, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Servier, and UCB. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = mar,
day = "1",
doi = "10.1016/j.molcel.2018.01.026",
language = "English (US)",
volume = "69",
pages = "744--756.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}