Machinery in motion: New insights into mitochondrial proteostasis

Abstract

ATP‐dependent AAA+ proteases are critical regulators of mitochondrial functions, playing crucial roles in the mitochondrial quality control response system. The past years have provided much structural insight into the molecular mechanisms associated with degradation of substrates by these proteolytic machines. Recent cryo‐electron microscopy (cryo‐EM) studies have provided critical insights into a conserved, AAA+‐mediated hand‐over‐hand substrate translocation mechanism required to processively engage, unfold, and degrade proteolytic substrates. However, the underlying mechanisms regulating their various activities are not well understood. Numerous prior studies suggest that AAA+ protease have evolved numerous layers of regulation to control or tune proteolytic activity to meet cellular needs. Herein, we present compelling biochemical and structural data that support a long‐range allosteric model linking substrate binding to proteolytic activity.