Mitochondrial MsrB2 serves as a switch and transducer for mitophagy

• Published in: EMBO molecular medicine Vol. 11; no. 8; pp. e10409 - n/a
• Main Authors: Lee, Seung Hee, Lee, Suho, Du, Jing, Jain, Kanika, Ding, Min, Kadado, Anis J, Atteya, Gourg, Jaji, Zainab, Tyagi, Tarun, Kim, Won‐ho, Herzog, Raimund I, Patel, Amar, Ionescu, Costin N, Martin, Kathleen A, Hwa, John
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2019; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Animals; Apoptosis; Autophagy; Blood Platelets - enzymology; Blood Platelets - pathology; Cell Line; Data analysis; Diabetes; Diabetes mellitus; Diabetes Mellitus - blood; Diabetes Mellitus - genetics; Diabetes Mellitus - pathology; EMBO21; EMBO27; Experiments; Female; Gene regulation; Heart; Humans; Insulin; Matrix protein; Methionine; methionine sulfoxide reductase; Methionine Sulfoxide Reductases - blood; Methionine Sulfoxide Reductases - deficiency; Methionine Sulfoxide Reductases - genetics; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins - blood; Microfilament Proteins - deficiency; Microfilament Proteins - genetics; Microscopy; Microtubule-Associated Proteins - blood; Mitochondria; Mitochondria - enzymology; Mitochondria - pathology; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Permeability Transition Pore; Mitophagy; Movement disorders; Mutation; Neurodegenerative diseases; Oxidation-Reduction; Oxidative Stress; Parkin protein; Parkinson Disease - blood; Parkinson Disease - genetics; Parkinson Disease - pathology; Parkinson's disease; Platelets; Proteins; Reactive oxygen species; Signal Transduction; Software; Transcription; Ubiquitin-Protein Ligases - blood; Ubiquitin-Protein Ligases - genetics; Ubiquitination; La Jolla California; United States > US; apoptosis; mitophagy; diabetes mellitus; methionine sulfoxide reductase; platelets
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201910409

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. Synopsis Mitophagy can be selectively switched on at sites of oxidatively damaged mitochondria: MsrB2 mediates these actions by switching on Parkin and transducing activation through LC3. This mechanism in found in diabetic platelets and may be important for Parkinson's disease. MsrB2 removes reduces oxidized methionine back to its native state and is induced in diabetic platelets. Parkin Met192 is oxidized in a high oxidative stress environment leading to Parkin dysfunction, aggregation and prevention of mitophagy. MsrB2 released from damaged mitochondria reduces MetO192 restoring Parkin's function (switch), allowing ubiquitination of MsrB2 and interaction with LC3 (transducer). The process of mitophagy is restored, protecting against apoptosis. The association of mutation of Met192 with Parkinson's disease led to studies that demonstrate a reduction in MsrB2 in patients with Parkinson's disease. Graphical Abstract Mitophagy can be selectively switched on at sites of oxidatively damaged mitochondria: MsrB2 mediates these actions by switching on Parkin and transducing activation through LC3. This mechanism in found in diabetic platelets and may be important for Parkinson's disease.