Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination.

Publication date: Feb 11, 2020

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, S.J., Lee, D., Yoo, H., Jun, K., Shin, H., and Chung, J. Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination. 23971. 2020 Proc Natl Acad Sci U S A.

Concepts Keywords
Apoptosis Locomotive dysfunction
Calcium Branches of biology
Dopaminergic Proteins
Drosophila Ion channels
KR Mitochondria
Locomotive Parkin
Missense Mutation Cell biology
Mitochondrial VDAC1
Mono PINK1
Neurons Mitophagy
Parkinson Protein families
Pathologies Mitochondrial calcium uniporter
Phenotypes Voltage-dependent anion channel
PINK1 Apoptosis
Polyubiquitination
Porin
Sci
Substrate
Transgenic
Ubiquitination

Semantics

Type Source Name
pathway KEGG Mitophagy
pathway KEGG Apoptosis
drug DRUGBANK Trihexyphenidyl
drug DRUGBANK Profenamine
drug DRUGBANK Calcium
disease MESH Parkinson disease
pathway KEGG Parkinson disease

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