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

Cell Reports

Pallavi Srivastava¹  Edith Serrano²  Pin-Chao Liao³  Liza A. Pon³  Dana M. Alessi Wolken⁴ 

[1] Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB T6G1H9, Canada;Department of Chemistry, Barnard College, Columbia University, New York, NY 10027, USA;Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA;Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA;

关键词: mitochondrial quality control;    oxidative stress;    reactive oxygen species;    proteostasis;    paraquat;    ubiquitin;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown