In the pathogenesis of diabetic retinopathy, superoxide generated by mitochondria are postulated to act as unifying molecules in the regulation of major pathways implicated in the development of diabetic retinopathy.
38 Mitochondria become dysfunctional and enlarged, and leak out cytochrome c in the cytosol, initiating the apoptotic machinery, and apoptosis of retinal capillary cells precedes the development of histopathology, which is the hallmark of diabetic retinopathy.
20,22,28,49 In the initial stages of the hyperglycemic insult, mtDNA repair and biogenesis are increased and this helps protect the electron transport chain system, but, with sustained insult, this protection mechanism becomes overwhelmed and the mtDNA is damaged, and the electron transport system is compromised.
22 In addition to increased ROS, mitochondrial lipid oxidation is also associated with its dysfunction, as fatty acids can interact with the electron chain components and bind to cytochrome c in complex III, interrupting the transport of electrons.
50 Consistent with 48 hours of glucotoxic insult showing no damage to the mtDNA and accelerating apoptosis,
22 here our results show that at this duration, the lipotoxic insult also has no effect on mitochondria damage. However, when the cells are exposed to glucolipotoxicity, mitochondria are damaged, as evidenced by significant increase in mtDNA damage and decrease in its transcription. This strongly suggests that the presence of both lipotoxic and glucotoxic insults together, accelerates damage to the mitochondria, and due to the compromised electron transport system, fueling of the vicious cycle of superoxide radicals is expedited. When the duration of the insult(s) is extended to 96 hours, although both glucotoxicity and glucolipotoxicity significantly damage mtDNA and its transcription, but, in contrast, lipotoxicity alone does not produce any significant effect. The reason for this discrepancy is unclear, but the possibility that further extension of lipotoxic insult could have damaged mtDNA cannot be ruled out.