Platelet Mitochondrial Dysfunction is Evident in Type 2 Diabetes in Association with Modifications of Mitochondrial Anti-Oxidant Stress Proteins

Abstract

Objective: Mitochondrial dysfunction and oxidative stress in insulin responsive tissues is implicated in the pathogenesis of type 2 diabetes. Whether these perturbations extend to other tissues and contribute to their pathophysiology is less well established. The objective of this study was to investigate platelet mitochondria to evaluate whether type 2 diabetes associated mitochondrial dysfunction is evident in circulating cells. Method: A pilot study of mitochondrial respiratory function and proteomic changes comparing platelets extracted from insulin sensitive (n=8) and type 2 diabetic subjects (n=7). Results: In-situ platelet mitochondria show diminished oxygen consumption and lower oxygen-dependent ATP synthesis in diabetic versus control subjects. Mass spectrometric identification and confirmatory immunoblot analysis identifies induction of the mitochondrial anti-oxidant enzymes superoxide dismutase 2 and thioredoxin-dependent peroxide reductase 3 in platelets of diabetic subjects. As oxidative stress upregulates anti-oxidant enzymes we assessed mitochondrial protein carbonylation as an index of oxidative-stress. Platelets of diabetic subjects exhibit significantly increased protein carbonylation compared to controls. Conclusions: As platelets are anuclear fragments of megakaryocytes, our data suggest that the bone marrow compartment in type 2 diabetic subjects is exposed to increased mitochondrial oxidative stress with upregulation of nuclear-encoded antioxidant mitochondrial enzymes. This ‘stress-signature’ in platelets of diabetic subjects is associated with a diminution of their mitochondrial contribution to energy production and support that mitochondrial perturbations in type 2 diabetes extends beyond the classical insulin responsive tissues. Platelets, as “accessible human tissue”, may be useful to measure the mitochondrial modulatory effects of emerging anti-diabetic therapeutics.

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Bioenergetics and the Oxidative Burst: Protocols for the Isolation and Evaluation of Human Leukocytes and Platelets

“…This is clinically important since mitochondrial dysfunction can initiate a series of cellular events that promote pro-inflammatory signaling pathways or lead to cell death. Several studies have characterized mitochondrial function of peripheral blood mononuclear cells and platelets in conditions such as fibromyalgia, diabetes, septic shock, and Alzheimer's disease [3][4][5][6][7] . For example, a recent study evaluated the bioenergetics of platelets as a marker for mitochondrial function and found that platelets from Type 2 diabetic patients had diminished mitochondrial oxygen consumption 7,8 .…”

“…Several studies have characterized mitochondrial function of peripheral blood mononuclear cells and platelets in conditions such as fibromyalgia, diabetes, septic shock, and Alzheimer's disease [3][4][5][6][7] . For example, a recent study evaluated the bioenergetics of platelets as a marker for mitochondrial function and found that platelets from Type 2 diabetic patients had diminished mitochondrial oxygen consumption 7,8 . From these findings and others, it is clear that monocytes, lymphocytes, neutrophils, and platelets can serve as surrogate markers of changes in bioenergetics under pathological conditions since they survey the systemic circulation and may reflect local and global metabolic changes.…”