Mitochondrial DNA and Diseases

Jiayun Hou, Mohmmad Eldeeb, Xiangdong Wang

Mutations or sequence aberrations in the Parkin gene are among the most common causes of autosomal recessive Parkinson's disorder (PD). Parkin, a cytoplasmic E3 ubiquitin ligase, is involved in mitochondrial quality control pathways, including mitochondrial fission and mitophagy by autophagy-related genes. Parkin mediates the covalent addition of ubiquitin (Ub) chains to Lys 6, Lys 11, and Lys 63 on diverse mitochondrial-related target proteins. USP30, a mitochondrial deubiquitinase, promotes mitochondrial fusion by mediating the deubiquitination of ubiquitylated forms of mitofusins, such as Mfn1 and Mfn2. USP30 preferentially mediates the removal of Ub chains from Lys 6 and Lys 11 on mitochondria-derived proteins. USP30 mediates the removal of the ubiquitin chains added by Parkin. It was demonstrated that overexpression of USP30 triggers the mitochondrial dynamic signaling toward elevated fusion and reduced fission and halts mitochondrial clearance via mitophagy. Although mounting lines of evidences reveal the pivotal role of Parkin in mitochondrial quality control pathways, the crucial role of deubiquitinases including the USP30 deubiquitinase is emerging. Herein, we review briefly the role of USP30 in the dynamic networks of mitochondrial quality control and its physiological implications.