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EMBO Mol Med. 2016 Jul 1;8(7):779-95. doi: 10.15252/emmm.201506046. Print 2016 Jul.

Inducing mitophagy in diabetic platelets protects against severe oxidative stress.

Author information

1
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.
2
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.
3
Section of Endocrinology & Metabolism, Yale University School of Medicine, New Haven, CT, USA.
4
Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA.
5
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.
6
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.

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.

KEYWORDS:

diabetes mellitus; mitophagy; oxidative stress; platelets

PMID:
27221050
PMCID:
PMC4931291
DOI:
10.15252/emmm.201506046
[Indexed for MEDLINE]
Free PMC Article

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