Figure 1.

Mitochondrial dysfunction and diabetic retinopathy. Hyperglycemia induces many metabolic abnormalities, including activation of the polyol pathway and protein kinase C and advanced glycation formation, and also activates cytosolic Nox2. These abnormalities lead to increased ROS, and increased ROS, in turn, fuel in the metabolic abnormalities. High glucose also auto-oxidizes, further increasing ROS levels. ROS activate MMP-9 and inhibit antioxidant enzyme Sod2, and while activated MMP-9 damages the mitochondria, inactivated Sod2 impairs scavenging of mitochondrial free radicals produced. The activity of complex III (of ETC) is decreased, further increasing ROS levels. mtDNA is oxidatively modified, mismatches are increased and mismatch repair enzyme Mlh1 is compromised, and the transcription of mtDNA is impaired, further contributing to free radical accumulation. The vicious cycle of free radicals continues to self-perpetuate. The damaged mitochondria increase cytochrome c leakage in the cytosol and activate the apoptotic machinery, resulting in the formation of acellular capillaries and pericyte ghosts, the early histopathological lesions of diabetic retinopathy.