TY - JOUR
T1 - Reciprocal Regulation of Mitofusin 2-Mediated Mitophagy and Mitochondrial Fusion by Different PINK1 Phosphorylation Events
AU - Li, Jiajia
AU - Dang, Xiawei
AU - Franco, Antonietta
AU - Dorn, Gerald W.
N1 - Publisher Copyright:
Copyright © 2022 Li, Dang, Franco and Dorn.
PY - 2022/5/12
Y1 - 2022/5/12
N2 - Mitochondrial repair is essential to metabolic homeostasis. Outer mitochondrial membrane mitofusin (MFN) proteins orchestrate mitochondrial fusion that opposes mitochondrial degeneration caused by senescence. Depending upon physiological context, MFN2 can either mediate mitochondrial fusion or recruit cytosolic Parkin to initiate mitophagic elimination. Because it is not clear how these events are counter-regulated we engineered and expressed MFN2 mutants that mimic phosphorylated or non-phosphorylatable MFN2 at its PINK1 phosphorylation sites: T111, S378, and S442. By interrogating mitochondrial fusion, polarization status, and Parkin binding/mitophagy as a function of inferred MFN2 phosphorylation, we discovered that individual MFN2 phosphorylation events act as a biological “bar-code”, directing mitochondrial fate based on phosphorylation site state. Experiments in Pink1 deficient cells supported a central role for PINK1 kinase as the pivotal regulator of MFN2 functionality. Contrary to popular wisdom that Parkin-mediated ubiquitination regulates MFN-mediated mitochondrial fusion, results in Prkn null cells demonstrated the dispensability of Parkin for MFN2 inactivation. These data demonstrate that PINK1-mediated phosphorylation is necessary and sufficient, and that Parkin is expendable, to switch MFN2 from fusion protein to mitophagy effector.
AB - Mitochondrial repair is essential to metabolic homeostasis. Outer mitochondrial membrane mitofusin (MFN) proteins orchestrate mitochondrial fusion that opposes mitochondrial degeneration caused by senescence. Depending upon physiological context, MFN2 can either mediate mitochondrial fusion or recruit cytosolic Parkin to initiate mitophagic elimination. Because it is not clear how these events are counter-regulated we engineered and expressed MFN2 mutants that mimic phosphorylated or non-phosphorylatable MFN2 at its PINK1 phosphorylation sites: T111, S378, and S442. By interrogating mitochondrial fusion, polarization status, and Parkin binding/mitophagy as a function of inferred MFN2 phosphorylation, we discovered that individual MFN2 phosphorylation events act as a biological “bar-code”, directing mitochondrial fate based on phosphorylation site state. Experiments in Pink1 deficient cells supported a central role for PINK1 kinase as the pivotal regulator of MFN2 functionality. Contrary to popular wisdom that Parkin-mediated ubiquitination regulates MFN-mediated mitochondrial fusion, results in Prkn null cells demonstrated the dispensability of Parkin for MFN2 inactivation. These data demonstrate that PINK1-mediated phosphorylation is necessary and sufficient, and that Parkin is expendable, to switch MFN2 from fusion protein to mitophagy effector.
KW - MFN2
KW - PINK1 kinase
KW - Parkin
KW - fusion
KW - mitochondrial quality control
KW - mitofusin regulation
KW - phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=85131333321&partnerID=8YFLogxK
U2 - 10.3389/fcell.2022.868465
DO - 10.3389/fcell.2022.868465
M3 - Article
C2 - 35646911
AN - SCOPUS:85131333321
SN - 2296-634X
VL - 10
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 868465
ER -