Regulation of the Stress-Activated Degradation of Mitochondrial Respiratory Complexes in Yeast

Abstract

Repair and removal of damaged mitochondria is a key process for eukaryotic cell homeostasis. Here we investigate in the yeast model how different protein complexes of the mitochondrial electron transport chain are subject to specific degradation upon high respiration load and organelle damage. We find that the turnover of subunits of the electron transport complex I equivalent and complex III is preferentially stimulated upon high respiration rates. Particular mitochondrial proteases, but not mitophagy, are involved in this activated degradation. Further mitochondrial damage by valinomycin treatment of yeast cells triggers the mitophagic removal of the same respiratory complexes. This selective protein degradation depends on the mitochondrial fusion and fission apparatus and the autophagy adaptor protein Atg11, but not on the mitochondrial mitophagy receptor Atg32. Loss of autophagosomal protein function leads to valinomycin sensitivity and an overproduction of reactive oxygen species upon mitochondrial damage. A specific event in this selective turnover of electron transport chain complexes seems to be the association of Atg11 with the mitochondrial network, which can be achieved by overexpression of the Atg11 protein even in the absence of Atg32. Furthermore, the interaction of various Atg11 molecules via the C-terminal coil domain is specifically and rapidly stimulated upon mitochondrial damage and could therefore be an early trigger of selective mitophagy in response to the organelles dysfunction. Our work indicates that autophagic quality control upon mitochondrial damage operates in a selective manner.

Mitophagy Improves Ethanol Tolerance in Yeast: Regulation by Mitochondrial Reactive Oxygen Species in Saccharomyces cerevisiae

“…In addition, several studies have reported that mitophagy promotes the elimination of ROS through the removal of damaged mitochondria [ 9 , 10 , 13 , 47 ]. Elevated respiration rates stimulate mitophagy degradation of the complex I equivalent and complex III of mtETC [ 27 ]. Therefore, the complex I equivalent and complex III are key mediators of ethanol stress related changes.…”

“…has reported that H 2 O 2 in the mitochondrial matrix has a signaling role in ethanol tolerance by Yap1p [ 5 ]. Additional studies indicate that mild ROS, as a signal molecule, regulates mitophagy [ 10 - 12 , 27 ].…”

Genetically controlled mtDNA editing prevents ROS damage by arresting oxidative phosphorylation

“…The K + -ionophore valinomycin induces overproduction of mitochondrial ROS and subsequent mitochondrial damage in yeast (Andrukhiv, Costa, West, & Garlid, 2006; Selivanov et al, 2008). This rapidly leads to formation of Atg11-containing autophagosomal structures at the mitochondrial surface, and these structures are instrumental for selective removal of complex I and complex III subunits (Timón-Gómez, Sanfeliu-Redondo, Pascual-Ahuir, & Proft, 2018). This is reminiscent of the mitochondria-derived vesicles (MDV) mechanism, which in mammals is responsible for local mitochondrial repair based on the mitochondrial export of 70 to 150 nm single- or double-membraned vesicles containing mitochondrial cargo that bud from the outer mitochondrial membrane, and which are subsequently degraded (Gustafsson & Dorn, 2019).…”