Mitochondrial dysfunction and oxidative stress in heart disease

Abstract

Beyond their role as a cellular powerhouse, mitochondria are emerging as integral players in molecular signaling and cell fate determination through reactive oxygen species (ROS). While ROS production has historically been portrayed as an unregulated process driving oxidative stress and disease pathology, contemporary studies reveal that ROS also facilitate normal physiology. Mitochondria are especially abundant in cardiac tissue; hence, mitochondrial dysregulation and ROS production are thought to contribute significantly to cardiac pathology. Moreover, there is growing appreciation that medical therapies designed to mediate mitochondrial ROS production can be important strategies to ameliorate cardiac disease. In this review, we highlight evidence from animal models that illustrates the strong connections between mitochondrial ROS and cardiac disease, discuss advancements in the development of mitochondria-targeted antioxidant therapies, and identify challenges faced in bringing such therapies into the clinic.

Fig. 1. Mitochondrial ROS generation.

Respiratory chain complexes I and III (orange) generate superoxide (O₂⁻) and hydrogen peroxide (H₂O₂) from molecular oxygen (O₂) within the mitochondrial intermembrane space. p66Shc (blue), in association with cytochrome c, participates in ROS signaling by producing hydrogen peroxide also within the intermembrane space. NADPH oxidase 4 (NOX4; red) localizes to the inner mitochondrial membrane, generating O₂⁻ and H₂O₂ within the mitochondrial matrix. Monoamine oxidase isoforms A and B (MAO-A/B; green) degrade monoamines to aldehydes and H₂O₂ in the outer mitochondrial membrane.

Fig. 2. ROS scavenging systems in the mitochondria.

Superoxide (O₂⁻) is produced at respiratory chain complexes I and III and is dismutated by SOD1 (intermembrane space and cytosol) and SOD2 (matrix) to generate hydrogen peroxide (H₂O₂). Catalase, localized to both the cytosol and the mitochondrial matrix, converts H₂O₂ into H₂O. Mitochondrial H₂O₂ detoxification can also be catalyzed by mitochondria-localized glutathione peroxidases (Gpx1 and Gpx4) and peroxiredoxins (PRX3 and PRX5). Gpxs oxidize glutathione (GSH) into GSSG, and reduced glutathione is regenerated by glutathione reductase (GR) using the reducing equivalents of NADPH. PRXs oxidize thioredoxin (Trx, with Trx2 being mitochondria-localized), and the reduced Trx pool is regenerated by the NADPH-dependent action of thioredoxin reductase (TRR; with TRR2 localized to the mitochondrial matrix).