Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities

Given their essential function in aerobic metabolism, mitochondria are intuitively of interest in regard to the pathophysiology of diabetes. Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes. Moreover, as a consequence of fuel oxidation, mitochondria generate considerable reactive oxygen species (ROS). Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications. In this review, we first present basic concepts underlying mitochondrial physiology. We then address mitochondrial function and ROS as related to diabetes. We consider different forms of diabetes and address both insulin secretion and insulin sensitivity. We also address the role of mitochondrial uncoupling and coenzyme Q. Finally, we address the potential for targeting mitochondria in the therapy of diabetes. Antioxid. Redox Signal. 12, 537–577.

1. Introduction

2. Basic Physiology

   1. Electron transport

   2. Reactive oxygen species and mitochondria

   3. Mitochondrial nitric oxide

   4. Role of calcium and the mitochondrial permeability transition pore

3. Assessing Mitochondrial Function

   1. Respiration and potential

   2. ATP production and the proton leak

   3. ROS production by isolated mitochondria

   4. Site specificity of mitochondrial superoxide production

   5. Mitochondrial ROS production in intact cells

   6. Oxidative damage to mitochondria in intact cells

4. Mitochondrial Metabolism and Diabetes

   1. General considerations

   2. Mitochondrial diabetes

   3. Type 1 and type 2 diabetes

      1. Mitochondrial number and morphology

      2. Fission/fusion

      3. Mitochondrial biogenesis

      4. Mitochondrial function in type 2 diabetes and insulin-resistant states

      5. Is mitochondrial impairment a cause of insulin resistance?

      6. Mitochondrial respiratory coupling and insulin release

      7. Mitochondrial function in insulin-deficient diabetes

      8. 538Diabetes and mitochondrial function in non–insulin-sensitive tissues

      9. Mitochondria and cell-fuel selectivity

      10. Diabetic cardiomyopathy and mitochondrial function

      11. Summary

5. Mitochondrial ROS and Diabetes

   1. ROS production and the cause of diabetes

      1. Oxidative damage and pancreatic islet β cells

      2. ROS and oxidative damage in insulin-sensitive target tissues

   2. ROS and the complications of diabetes

      1. Non–insulin-sensitive tissues (retina, renal, neural cells)

      2. ROS and vascular cells

   3. Summary

6. Mitochondrial Membrane Potential and Diabetes

   1. Role of uncoupling proteins

   2. Does membrane potential actually protect against superoxide production?

   3. Summary

7. Coenzyme Q and Diabetes

8. Therapeutic Implications

   1. Improving mitochondrial metabolism

      1. Lifestyle modification

      2. Pharmacologic intervention

   2. Controlling ROS production and oxidative damage

   3. Mitochondria-targeted antioxidants

   4. Metabolic effects of mitochondria-targeted antioxidants

   5. Mitochondria-targeted antioxidant peptides

   6. Targeting superoxide

9. Summary