한빛사 논문
Seung Hee Lee1,2,* , Suho Lee3, Jing Du1, Kanika Jain1, Min Ding1, Anis J Kadado1, Gourg Atteya1, Zainab Jaji1, Tarun Tyagi1, Won-ho Kim2, Raimund I Herzog4, Amar Patel5, Costin N Ionescu6, Kathleen A Martin1 & John Hwa1,**
1 Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
2 Division of Cardiovascular Diseases, Center for Biomedical Sciences, National Institute of Health, Cheongju, Chungbuk, Korea
3 Departments of Neurology and Neurobiology, Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA
4 Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
5 Division of Movement Disorders, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT, USA
6 Yale Cardiovascular Medicine, Department of Internal Medicine, Yale-New Haven Hospital, New Haven, CT, USA
*Corresponding author
**Corresponding author
Abstract
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.
Keywords : apoptosis; diabetes mellitus; methionine sulfoxide reductase; mitophagy; platelets
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