Cell Reports
Volume 32, Issue 2, 14 July 2020, 107902
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Mitochondria-Associated Degradation Pathway (MAD) Function beyond the Outer Membrane

https://doi.org/10.1016/j.celrep.2020.107902Get rights and content
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Highlights

  • The MAD is critical for mitochondrial quality control under mitochondrial oxidative stress

  • Inhibition of the MAD results in reduction in chronological lifespan

  • MAD substrates are not only on the mitochondrial surface but also within the organelle

Summary

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.

Keywords

mitochondrial quality control
oxidative stress
reactive oxygen species
proteostasis
paraquat
ubiquitin
proteasome
mitophagy
chronological lifespan
Saccharomyces cerevisiae

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