The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway

• Published in: Human molecular genetics Vol. 24; no. 9; pp. 2528 - 2538
• Main Authors: Gao, Feng, Chen, Dong, Si, Jianmin, Hu, Qingsong, Qin, Zhenghong, Fang, Ming, Wang, Guanghui
• Format: Journal Article
• Language: English
• Published: England 01.05.2015
• Subjects: Animals; Cell Line; Electron Transport Complex I - metabolism; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mitochondrial Degradation - genetics; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Models, Biological; Muscles - metabolism; Muscles - ultrastructure; Parkinson Disease - genetics; Parkinson Disease - metabolism; Protein Kinases - metabolism; Proteins - metabolism; Proteolysis; Signal Transduction; Substrate Specificity; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddv017

Mitochondrial dysfunction plays important roles in Parkinson's disease (PD) and the degradation of the damaged mitochondria by the mitochondria quality control system is important for dopaminergic (DA) neuronal survival. BNIP3L/Nix is a mitochondrial outer membrane protein that is required for the selective clearance of mitochondria. Here, we found that the mitochondrial protein BNIP3L acts downstream of the PINK1/PARK2 pathway to induce mitophagy. BNIP3L is a substrate of PARK2 to drive PARK2-mediated mitophagy. The ubiquitination of BNIP3L by PARK2 recruits NBR1 to mitochondria, thereby targeting mitochondria for degradation. BNIP3L rescues mitochondrial defects in pink1 mutant Drosophila but not in park mutant Drosophila, indicating that the clearance of mitochondria induced by BNIP3L depends on the presence of PARK2. In cells intoxicated with mitochondrial complex I inhibitors rotenone, 6-OHDA or MPP(+), the disrupted mitochondria are not appropriately eliminated by mitophagy due to the improper degradation of BNIP3L. Thus, our study demonstrates that BNIP3L, as a substrate of PARK2, promotes mitophagy in the PINK1/PARK2 pathway associated with PD pathogenesis.