Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination.
VDAC1 is a critical substrate of Parkin responsible for the regulation of mitophagy and apoptosis. Here, we demonstrate that VDAC1 can be either mono- or polyubiquitinated by Parkin in a PINK1-dependent manner. VDAC1 deficient with polyubiquitination (VDAC1 Poly-KR) hampers mitophagy, but VDAC1 deficient with monoubiquitination (VDAC1 K274R) promotes apoptosis by augmenting the mitochondrial calcium uptake through the mitochondrial calcium uniporter (MCU) channel. The transgenic flies expressing Drosophila Porin K273R, corresponding to human VDAC1 K274R, show Parkinson disease (PD)-related phenotypes including locomotive dysfunction and degenerated dopaminergic neurons, which are relieved by suppressing MCU and mitochondrial calcium uptake. To further confirm the relevance of our findings in PD, we identify a missense mutation of Parkin discovered in PD patients, T415N, which lacks the ability to induce VDAC1 monoubiquitination but still maintains polyubiquitination. Interestingly, Drosophila Parkin T433N, corresponding to human Parkin T415N, fails to rescue the PD-related phenotypes of Parkin-null flies. Taken together, our results suggest that VDAC1 monoubiquitination plays important roles in the pathologies of PD by controlling apoptosis.
['Ham|Su Jin|SJ|', 'Lee|Daewon|D|', 'Yoo|Heesuk|H|', 'Jun|Kyoungho|K|', 'Shin|Heejin|H|', 'Chung|Jongkyeong|J|']
D000818:Animals D017209:Apoptosis D002118:Calcium D004330:Drosophila D005260:Female D006801:Humans D051379:Mice D018345:Mice, Knockout D008928:Mitochondria D063306:Mitophagy D010300:Parkinson Disease D011494:Protein Kinases D044767:Ubiquitin-Protein Ligases D054875:Ubiquitination D050995:Voltage-Dependent Anion Channel 1
apoptosis Parkin VDAC1 Parkinson disease PINK1