Journal Article

Inducing mitophagy in diabetic platelets protects against severe oxidative stress

Jin, Yu, Spollett, Geralyn, Tang, Wai Ho, Lee, Seung Hee, Leslie, Kristen L, Mannam, Praveen, Srivastava, Anup, Atteya, Gourg, Hwa, John, Martin, Kathleen A, Stitham, Jeremiah, Lee, Suho, Xiang, Yaozu, Du, Jing, Wang, Dandan, Ostriker, Allison

2016

Overview

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. Synopsis Under conditions of the severe oxidative stress commonly associated with diabetes mellitus in patients, induction of platelet mitophagy protects the platelet from apoptosis by removing the damaged mitochondria and preserves platelets function. Autophagy and mitophagy are increased in diabetic platelets. Mitophagy is induced in platelets through an ROS/JNK‐mediated pathway. Mitophagy induction serves to protect diabetic platelets from oxidative stress‐induced apoptosis. Mitophagy induction protects against increased thrombosis associated with diabetes mellitus. Graphical Abstract Under conditions of the severe oxidative stress commonly associated with diabetes mellitus in patients, induction of platelet mitophagy protects the platelet from apoptosis by removing the damaged mitochondria and preserves platelets function.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Apoptosis / Autophagy / Blood Platelets - pathology / Diabetes / Diabetes mellitus / Diabetes Mellitus - pathology / EMBO18 / EMBO21 / EMBO46 / Heart attacks / Homeostasis / Humans / Hyperglycemia / Insulin / MAP Kinase Signaling System / Mitochondria / Mitophagy / Morbidity / Oxidative Stress / p53 Protein / Phagocytosis / Phosphorylation / Platelets / Protein Processing, Post-Translational / Proteins / Research Article / Roles / Software / Thrombosis / Transcription / Tumor Suppressor Protein p53 - metabolism