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Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
Author(s) -
Bernardini Jonathan P,
Brouwer Jason M,
Tan Iris KL,
Sandow Jarrod J,
Huang Shuai,
Stafford Che A,
Bankovacki Aleksandra,
Riffkin Christopher D,
Wardak Ahmad Z,
Czabotar Peter E,
Lazarou Michael,
Dewson Grant
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899916
Subject(s) - mitophagy , biology , parkin , apoptosis , microbiology and biotechnology , function (biology) , pink1 , autophagy , mitochondrion , genetics , parkinson's disease , medicine , disease
Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH 3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX ‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK ‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK 1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect.