The mitochondrial fusion–fission process is important in constantly changing energy demands of the cell. Their shape is regulated by balance between fusion and fission, and function is controlled by multiple proteins that mediate remodeling of the outer and inner mitochondrial membranes. Fusion allows the spreading of metabolites, protein, and DNA throughout the network and protects cells from the toxic effects of damaged mitochondrial DNA by allowing functional complementation between two adjacent mitochondria.
21 For maintaining mitochondrial morphology and metabolism, Mfn2 is considered crucial, and deficiency is lethal.
22 In contrast, inactivation of fusion induces the loss of mtDNA, and mitochondria fission is related to autophagy and Bax-mediated apoptosis.
7,8 Fission proteins Fis1 and Dnm1l are the core components of the mitochondrial fission machinery. Excessive mitochondrial fission, induced by oxidative and nitrosative stress, serves as an important and early event in neurodegenerative diseases.
23 In our study, diabetes decreased the gene expression of
Mfn2 in the retina. Our data, however, show a dichotomy: Diabetes also decreased the expression of
Fis1 but increased the expression of
Dnm1l. Although Fis1 is located throughout the outer membrane,
Dnm1l is in the cytosol and is recruited at the point of fission.
24 Others have shown that Fis1 does not directly activate Bax, but it can induce calcium-dependent mitochondrial dysfunction, and this bifunctional protein can independently regulate mitochondrial fragmentation.
25 The assembly of Dnm1l is necessary for fission activity, and apoptotic stimulation recruits it to the mitochondrial outer membrane, where it is co-localized with Bax and Mfn2 at the fission site.
26 The recruitment of Dnm1l to mitochondria could be facilitated in a mitochondrial fission factor (Mff)–dependent manner and mitochondrial-dynamic proteins of 49 and 51 kDa (MiD49/51), anchored in the mitochondrial outer membrane, help directly recruit Dnm1l to the mitochondrial surface. However, recruitment could also be facilitated in an Mff/Mfn2-independent manner by interacting with MiD51, which could act both as an inhibitor of fission and a promoter of fusion.
27 –30 The role of these proteins in regulating Dnm1l in the pathogenesis of diabetic retinopathy remains unclear. Our results clearly suggest that the fusion–fission machinery of the retinal mitochondria is severely dysfunctional in diabetes, and this factor may contribute to the alterations in the ultrastructure of the mitochondria and also to the decreased number of mitochondria. In support of this conclusion, others have shown increased Dnm1l in neuron and endothelial cells with fragmented mitochondria in diabetic rodents,
31,32 and our recent study has documented that the mitochondria copy number is significantly decreased in the retinas of rats that are diabetic for 12 months.
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