Regulation of Mitochondrial Clearance via Factors on the Endoplasmic Reticulum Akinori Eiyama1, Mashun Onishi1, Sachiyo Nagumo1, Koji Okamoto1* 1Laboratory of Mitochondrial Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
Selective clearance of excess or unhealthy mitochondria is a fundamental process conserved from yeast to humans, contributing to mitochondrial quantity and quality control. This catabolic event primarily depends on autophagy, a cellular self-eating pathway that mediates transport of cytoplasmic components to lysosomes for degradation, and is thus called mitophagy. Defects in mitophagy are associated with a myriad of disorders such as mitochondrial malfunction, neurodegeneration, heart/liver failure, aging, and cancer, underscoring the physiological relevance. Although previous studies have revealed multiple key molecules that establish the selectivity of mitophagy, how cells coordinate mitochondrial clearance and other cellular functions remains poorly understood. Using budding yeast as a model organism, we provide evidence suggesting an unexpected link between mitophagy and the endoplasmic reticulum (ER) protein biogenesis/degradation. We found that mitophagy was suppressed in the absence of a heterodimeric ER membrane protein insertase of the GET (guided entry of tail-anchored proteins) pathway. Conversely, mitophagy induction was accelerated in cells lacking a transmembrane ubiquitin E3 ligase of the ERAD (ER-associated protein degradation) systems. Possible mechanisms regulating mitochondrial clearance through the heterologous organellar factors will be discussed.
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