Mitochondrial MsrB2 serves as a switch and transducer for mitophagy.
Mitophagy can selectively remove damaged toxic mitochondria, protecting a cell from apoptosis. The molecular spatial-temporal mechanisms governing autophagosomal selection of reactive oxygen species (ROS)-damaged mitochondria, particularly in a platelet (no genomic DNA for transcriptional regulation), remain unclear. We now report that the mitochondrial matrix protein MsrB2 plays an important role in switching on mitophagy by reducing Parkin methionine oxidation (MetO), and transducing mitophagy through ubiquitination by Parkin and interacting with LC3. This biochemical signaling only occurs at damaged mitochondria where MsrB2 is released from the mitochondrial matrix. MsrB2 platelet-specific knockout and in vivo peptide inhibition of the MsrB2/LC3 interaction lead to reduced mitophagy and increased platelet apoptosis. Pathophysiological importance is highlighted in human subjects, where increased MsrB2 expression in diabetes mellitus leads to increased platelet mitophagy, and in platelets from Parkinson's disease patients, where reduced MsrB2 expression is associated with reduced mitophagy. Moreover, Parkin mutations at Met192 are associated with Parkinson's disease, highlighting the structural sensitivity at the Met192 position. Release of the enzyme MsrB2 from damaged mitochondria, initiating autophagosome formation, represents a novel regulatory mechanism for oxidative stress-induced mitophagy.
['Lee|Seung Hee|SH|0000-0003-3642-1416', 'Lee|Suho|S|', 'Du|Jing|J|', 'Jain|Kanika|K|', 'Ding|Min|M|', 'Kadado|Anis J|AJ|', 'Atteya|Gourg|G|', 'Jaji|Zainab|Z|', 'Tyagi|Tarun|T|', 'Kim|Won-Ho|WH|', 'Herzog|Raimund I|RI|', 'Patel|Amar|A|', 'Ionescu|Costin N|CN|', 'Martin|Kathleen A|KA|', 'Hwa|John|J|0000-0001-7366-2628']
D000818:Animals D001792:Blood Platelets D002460:Cell Line D003920:Diabetes Mellitus D005260:Female D006801:Humans D051150:Methionine Sulfoxide Reductases D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008840:Microfilament Proteins D008869:Microtubule-Associated Proteins D008928:Mitochondria D033681:Mitochondrial Membrane Transport Proteins D000083162:Mitochondrial Permeability Transition Pore D063306:Mitophagy D009154:Mutation D010084:Oxidation-Reduction D018384:Oxidative Stress D010300:Parkinson Disease D015398:Signal Transduction D044767:Ubiquitin-Protein Ligases D054875:Ubiquitination
mitophagy apoptosis platelets diabetes mellitus methionine sulfoxide reductase