Mitochondria-Associated Proteostasis

Mitochondria are essential organelles in eukaryotes. Most mitochondrial proteins are encoded by the nuclear genome and translated in the cytosol. Nuclear-encoded mitochondrial proteins need to be imported, processed, folded, and assembled into their functional states. To maintain protein homeostasis (proteostasis), mitochondria are equipped with a distinct set of quality control machineries. Deficiencies in such systems lead to mitochondrial dysfunction, which is a hallmark of aging and many human diseases, such as neurodegenerative diseases, cardiovascular diseases, and cancer. In this review, we discuss the unique challenges and solutions of proteostasis in mitochondria. The import machinery coordinates with mitochondrial proteases and chaperones to maintain the mitochondrial proteome. Moreover, mitochondrial proteostasis depends on cytosolic protein quality control mechanisms during crises. In turn, mitochondria facilitate cytosolic proteostasis. Increasing evidence suggests that enhancing mitochondrial proteostasis may hold therapeutic potential to protect against protein aggregation–associated cellular defects.