Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease

Abstract

The metabolic syndrome is a constellation of metabolic disorders including obesity, hypertension, and insulin resistance, components which are risk factors for the development of diabetes, hypertension, cardiovascular, and renal disease. Pathophysiological abnormalities that contribute to the development of the metabolic syndrome include impaired mitochondrial oxidative phosphorylation and mitochondrial biogenesis, dampened insulin metabolic signaling, endothelial dysfunction, and associated myocardial functional abnormalities. Recent evidence suggests that impaired myocardial mitochondrial biogenesis, fatty acid metabolism, and antioxidant defense mechanisms lead to diminished cardiac substrate flexibility, decreased cardiac energetic efficiency, and diastolic dysfunction. In addition, enhanced activation of the renin-angiotensin-aldosterone system and associated increases in oxidative stress can lead to mitochondrial apoptosis and degradation, altered bioenergetics, and accumulation of lipids in the heart. In addition to impairments in metabolic signaling and oxidative stress, genetic and environmental factors, aging, and hyperglycemia all contribute to reduced mitochondrial biogenesis and mitochondrial dysfunction. These mitochondrial abnormalities can predispose a metabolic cardiomyopathy characterized by diastolic dysfunction. Mitochondrial dysfunction and resulting lipid accumulation in skeletal muscle, liver, and pancreas also impede insulin metabolic signaling and glucose metabolism, ultimately leading to a further increase in mitochondrial dysfunction. Interventions to improve mitochondrial function have been shown to correct insulin metabolic signaling and other metabolic and cardiovascular abnormalities. This review explores mechanisms of mitochondrial dysfunction with a focus on impaired oxidative phosphorylation and mitochondrial biogenesis in the pathophysiology of metabolic heart disease.

Fig. 1

Role of the RAAS in mitochondrial dysfunction. Ang II and aldosterone inhibit insulin metabolic signaling that results in impairments in glucose transport/utilization in cardiovascular tissue as well as other insulin-sensitive tissue. The ensuing increases in oxidative stress reduce glucose transport/utilization as well as mitochondrial ATP generation. Ultimately, these changes will contribute to long-term endothelial (reduced NO) and cardiomyocyte diastolic dysfunction. AP-1 activator protein 1, AT₁R Ang type 1 receptor, Ang II angiotensin II, ERK extracellular signal-regulated kinases, FFA free fatty acid, HIF1 hypoxia-inducible factor 1, IRS-1 insulin resistance substrate 1, JNK JUN NH₂-terminal kinases, NF-kB nuclear factor-kB, MR mineralocorticoid receptor, PI3-K phosphoinositol 3-kinase, ROS reactive oxygen species

Fig. 2

Normal mitochondrial respiratory chain and nutrient metabolism. Reducing agents (NADH or FADH₂) are generated from glycolysis and Krebs cycle of glucose metabolism and β-oxidation of fatty acids. While NADH or FADH₂ are oxidized to NAD⁺ or FAD, the electrons are carried to complex I (NADH-ubiquinone reductase), complex II (succinated ubiquinone reductase), complex III (ubiquinone-cytochrome c reductase), complex IV (cytochrome oxidase), and finally to O₂, which produces H₂O. Oxidation of NADH or FADH₂ generates protons that are pumped to intermembrane space through complex I, III, and IV. The pumped protons increase electrochemical gradient across the membrane. This proton gradient is the driving force for F0F1-ATPase (ATP synthase) to produce ATP

Fig. 3

Myocardial mitochondrial biogenesis. a Normal cardiac ultrastructure of mitochondria and intercalated disc on ultrastructural analysis utilizing transmission electron microscopy. Note the orderly and linearly arranged sarcomeres and subsarcolemmal (sarcoplasmic reticulum) mitochondria. b Mitochondrial changes in the insulin-resistant Ren2 rat which displays diastolic dysfunction. c Biogenesis of small morphologically abnormal mitochondria depicted in stylized version