Abstract
At the core of proper mitochondrial functionality is the maintenance of its structure and morphology. Physical changes in mitochondrial structure alter metabolic pathways inside mitochondria, affect mitochondrial turnover, disturb mitochondrial dynamics, and promote mitochondrial fragmentation, ultimately triggering apoptosis. In high glucose condition, increased mitochondrial fragmentation contributes to apoptotic death in retinal vascular and Müller cells. Although alterations in mitochondrial morphology have been detected in several diabetic tissues, it remains to be established in the vascular cells of the diabetic retina. From a mechanistic standpoint, our current work supports the notion that increased expression of fission genes and decreased expression of fusion genes are involved in promoting excessive mitochondrial fragmentation. While mechanistic insights are only beginning to reveal how high glucose alters mitochondrial morphology, the consequences are clearly seen as release of cytochrome c from fragmented mitochondria triggers apoptosis. Current findings raise the prospect of targeting excessive mitochondrial fragmentation as a potential therapeutic strategy for treatment of diabetic retinopathy. While biochemical and epigenetic changes have been reported to be associated with mitochondrial dysfunction, this review focuses on alterations in mitochondrial morphology, and their impact on mitochondrial function and pathogenesis of diabetic retinopathy.
Highlights
Time-lapse videography of live cells has documented spectacular mitochondrial movement within a cell where each mitochondrion movement occurs in the direction of its longitudinal axis
Current understanding suggests that alteration in fusion and fission gene expression may negatively impact mitochondrial structure. These findings suggest that high glucose-induced mitochondrial structural damage involving excessive mitochondrial fragmentation plays a critical role in promoting apoptotic cell death associated with diabetic retinopathy
Inhibition of mtCx43 activity in isolated mitochondria promoted cytochrome c release [70], suggesting that mtCx43 changes may contribute to overall mitochondrial dysfunction evident in retinal vascular cells associated with diabetic retinopathy
Summary
Time-lapse videography of live cells has documented spectacular mitochondrial movement within a cell where each mitochondrion movement occurs in the direction of its longitudinal axis. Subtle changes in mitochondrial shape seen as local narrowing/contractions and thickening/relaxations reflect a “worm-like swimming” movement coupled with a remarkable phenomenon of fission and fusion, orchestrating the dynamic nature of the mitochondrial network. These changes in mitochondrial structure are important to the normal function of cells. Mitochondrial shape change can rapidly flip from facilitating normal cell function to promoting apoptotic cell death. The ability of high glucose (HG) condition to promote mitochondrial fragmentation has captured the interest of several labs including ours. In HG condition, mitochondrial fragmentation led to compromised metabolic changes, promoting apoptosis [1,2,3]
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