Chapter 5 - Cdc48 AAA ATPase Regulates Protein Dynamics and Turnover in Mitochondria

Abstract

Protein degradation contributes to not only the removal of abnormal proteins but also the regulation of biological reactions. The AAA ATPase Cdc48 and the proteasome are widely involved in protein degradation in the cytosol. Cdc48 and the proteasome also regulate quality control of mitochondrial outer membrane proteins including antiapoptotic factors and mitofusins that are responsible for tethering of the mitochondrial outer membrane during fusion events. ATPase-deficient mutants of Cdc48 inhibit mitochondrial fusion and collectively, it has been proposed that mitofusin degradation is required for the progression of mitochondrial membrane fusion. In contrast, recent evidence suggests that Cdc48 may mediate mitochondrial fusion by disassembly of mitofusin tethering complexes. The cytosolic AAA protein thus controls mitochondrial integrity by regulating not only protein stability but also complex formation. This review provides a detailed exploration of how Cdc48 functions to regulate mitochondrial protein quality and morphology.