Mitochondria-Associated Degradation Pathway (MAD) Function beyond the Outer Membrane.

Cell Reports
Pin-Chao LiaoLiza A Pon

Abstract

The mitochondria-associated degradation pathway (MAD) mediates ubiquitination and degradation of mitochondrial outer membrane (MOM) proteins by the proteasome. We find that the MAD, but not other quality-control pathways including macroautophagy, mitophagy, or mitochondrial chaperones and proteases, is critical for yeast cellular fitness under conditions of paraquat (PQ)-induced oxidative stress in mitochondria. Specifically, inhibition of the MAD increases PQ-induced defects in growth and mitochondrial quality and decreases chronological lifespan. We use mass spectrometry analysis to identify possible MAD substrates as mitochondrial proteins that exhibit increased ubiquitination in response to PQ treatment and inhibition of the MAD. We identify candidate substrates in the mitochondrial matrix and inner membrane and confirm that two matrix proteins are MAD substrates. Our studies reveal a broader function for the MAD in mitochondrial protein surveillance beyond the MOM and a major role for the MAD in cellular and mitochondrial fitness in response to chronic, low-level oxidative stress in mitochondria.

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Citations

Sep 24, 2020·International Journal of Molecular Sciences·Mafalda Escobar-Henriques, Vincent Anton
Dec 31, 2020·STAR Protocols·Pin-Chao LiaoLiza A Pon
Mar 5, 2021·Developmental Cell·Matthew Yoke Wui NgAnne Simonsen
Aug 31, 2020·Biochimica Et Biophysica Acta. Bioenergetics·Cynthia AlsayyahMickael M Cohen
Sep 9, 2021·Journal of Applied Microbiology·Tatsuya KatoEnoch Y Park

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Datasets Mentioned

BETA
GSE150804

Methods Mentioned

BETA
ubiquitination
deubiquitination
co-immunoprecipitation
RNA-seq
PCR
electrophoresis
Fusion Tribrid
Acetylation
Deamination
pull-down

Software Mentioned

GraphPad
STAR aligner
Volocity
Trimmomatic
ENSEMBL
Andromeda
MaxQuant
MaxLFQ
Subread
DESeq2

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