Mitochondria in the diabetic heart

Abstract

Diabetes mellitus increases the risk of developing cardiovascular diseases such as coronary artery disease and heart failure. Studies have shown that the heart failure risk is increased in diabetic patients even after adjusting for coronary artery disease and hypertension. Although the cause of this increased heart failure risk is multifactorial, increasing evidence suggests that derangements in cardiac energy metabolism play an important role. In particular, abnormalities in cardiomyocyte mitochondrial energetics appear to contribute substantially to the development of cardiac dysfunction in diabetes. This review will summarize these abnormalities in mitochondrial function and discuss potential underlying mechanisms.

Figure 1

Fatty acid-induced mitochondrial uncoupling and impaired cardiac efficiency. In Type 2 diabetes, increased delivery of fatty acids to the heart may result in increased fatty acid uptake and oxidation. The resulting increase in reducing equivalent delivery to the respiratory chain may increase ROS production, leading to activation of UCPs and proton leak via ANT. The resulting increase in mitochondrial uncoupling leads to increased mitochondrial O₂ consumption, thereby increasing fatty acid oxidation even further. Since the increase in O₂ consumption results from mitochondrial uncoupling, ATP synthesis would not increase proportionately, resulting in reduced cardiac efficiency, subsequent cardiac energy deficit, and ultimately contractile dysfunction. FAO, fatty acid oxidation; GO, glucose oxidation; ROS, reactive oxygen species, UCP, uncoupling protein; ANT, adenine nucleotide translocator.

Figure 2

Impaired mitochondrial Ca²⁺ handling. Impaired sarcoplasmic reticulum Ca²⁺ release (A) or reduced re-uptake (B) may limit peak cytosolic Ca²⁺ levels, which may limit intramitochondrial Ca²⁺ accumulation during contraction. This may reduce the attendant increase in dehydrogenase activation and ATP synthesis. Reduced ATP synthesis and lower cytosolic Ca²⁺ transients may both contribute to contractile dysfunction or impaired relaxation in diabetes. PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid; DHPR, dihydropyridine receptor; RyR, ryanodine receptor.

Figure 3

Proposed and hypothetical/under-explored mechanisms leading to cardiac mitochondrial dysfunction in diabetes.