Mitochondrial AAA proteases: A stairway to degradation

Mitochondrial protein quality control requires the action of proteases to remove damaged or unnecessary proteins and perform key regulatory cleavage events. Important components of the quality control network are the mitochondrial AAA proteases, which capture energy from ATP hydrolysis to destabilize and degrade protein substrates on both sides of the inner membrane. Dysfunction of these proteases leads to the breakdown of mitochondrial proteostasis and is linked to the development of severe human diseases. In this review, we will describe recent insights into the structure and motions of the mitochondrial AAA proteases and related enzymes. Together, these studies have revealed the mechanics of ATP-driven protein destruction and significantly advanced our understanding of how these proteases maintain mitochondrial health.