title: Inducing mitophagy in diabetic platelets protects against severe oxidative stress.
abstract: Diabetes mellitus (DM) is a growing international concern. Considerable mortality and morbidity associated with diabetes mellitus arise predominantly from thrombotic cardiovascular events. Oxidative stress-mediated mitochondrial damage contributes significantly to enhanced thrombosis in DM A basal autophagy process has recently been described as playing an important role in normal platelet activation. We now report a substantial mitophagy induction (above basal autophagy levels) in diabetic platelets, suggesting alternative roles for autophagy in platelet pathology. Using a combination of molecular, biochemical, and imaging studies on human DM platelets, we report that platelet mitophagy induction serves as a platelet protective mechanism that responds to oxidative stress through JNK activation. By removing damaged mitochondria (mitophagy), phosphorylated p53 is reduced, preventing progression to apoptosis, and preserving platelet function. The absence of mitophagy in DM platelets results in failure to protect against oxidative stress, leading to increased thrombosis. Surprisingly, this removal of damaged mitochondria does not require contributions from transcription, as platelets lack a nucleus. The considerable energy and resources expended in "prepackaging" the complex mitophagy machinery in a short-lived normal platelet support a critical role, in anticipation of exposure to oxidative stress.
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Stitham
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Gourg
authors.initials: G
authors.lastname: Atteya
authors.affiliation: Departments of Neurology and Neurobiology, Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Suho
authors.initials: S
authors.lastname: Lee
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Yaozu
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Leslie
authors.affiliation: Section of Endocrinology & Metabolism, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Geralyn
authors.initials: G
authors.lastname: Spollett
authors.affiliation: Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Anup
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Mannam
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Ostriker
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Martin
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China waiho.tang@yale.edu john.hwa@yale.edu.
authors.forename: Wai Ho
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA waiho.tang@yale.edu john.hwa@yale.edu.
authors.forename: John
authors.identifier: 0000-0001-7366-2628
authors.initials: J
authors.lastname: Hwa
mesh_terms: D017209:Apoptosis; D001792:Blood Platelets / Q000473:pathology*; D003920:Diabetes Mellitus / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System; D063306:Mitophagy; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: diabetes mellitus; mitophagy; oxidative stress; platelets