Mitochondrial pathophysiology, reactive oxygen species, and cardiovascular diseases

Abstract

This article discusses mitochondrial pathophysiology, reactive oxygen species, and cardiovascular diseases. Mitochondrial respiratory chains are responsible for energy metabolism/ATP production through the tricyclic antidepressant cycle, coupling of oxidative phosphorylation, and electron transfer. The mitochondrion produces reactive oxygen species as "side products" of respiration. The mitochondrial derived reactive oxygen species is involved in the pathogenesis of various clinical disorders including heart failure, hypoxia, ischemia/reperfusion injury, diabetes, neurodegenerative diseases, and the physiologic process of aging. Observational and mechanistical studies of these pathologic roles of mitochondria are discussed in depth in this article.

Figure 1. Mitochondrial ROS and antioxidant network

Electron leak to oxygen through complexes I and III can generate superoxide anion. The rate of O₂⁻ production is affected by mitochondrial metabolic state. Recent studies suggest that complex I releases O₂⁻ into the matrix while complex III can release O₂⁻ into the matrix as well as the intermembrane space. Superoxide anion can be converted to H₂O₂ by mitochondrial matrix enzyme MnSOD or by CuZnSOD in the intermembrane space. H₂O₂ is more stable than O₂⁻ and can diffuse out of the mitochondrion and into the cytosol. O₂⁻ can also react with another free radical, nitric oxide (NO⁻), formed by mitochondrial nitric oxide synthase, to generate the highly reactive peroxynitrite (ONOO⁻). However, mitochondria are normally protected from oxidative damage by a multilayer network of mitochondrial antioxidant system. H₂O₂ can be readily converted to water by mitochondrial glutathione peroxidase (GP), which oxidizes reduced glutathione (GSH) to oxidized glutathione (GSSG). In addition to GSH, mitochondria have other small thiols such as α-tocopherol and glutaredoxin which play important roles in thiol redox control and scavenging lipid peroxyl radicals. Data from .

Figure 2. Mitochondrial ROS and apoptosis

ETC generated ROS induces oxidative stress which leads to upregulation of p53 and FAS gene expression. FAS activation will initiate death receptor pathway of apoptosis. However, p53 gene activation will trigger mitochondrial pathway of apoptosis by induction of cytochrome c release. Both death receptor and mitochondrial pathways are integrated into caspase cascade for apoptosis. Depending on the availability of intracellular ATP, the cell death pathway may switch from apoptosis to necrosis. While apoptosis is the predominant cell death pathway in the presence of adequate ATP .