Role of Mitochondria Biogenesis in the Metabolic Memory Associated with the Continued Progression of Diabetic Retinopathy and Its Regulation by Lipoic Acid

PURPOSE. Termination of hyperglycemia does not arrest the progression of diabetic retinopathy, and retinal mitochondrial DNA (mtDNA) remains damaged, resulting in a continuous cycle of mitochondrial dysfunction. This study is to investigate the role of mitochondria biogenesis (regulated by nuclear mitochondrial signaling) in the metabolic memory phenomenon. METHODS. Mitochondria DNA copy number, functional integrity, and biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1 alpha [PGC1], nuclear respiratory factor 1 [NRF1], mitochondrial transcriptional factor [TFAM]) were analyzed in the retina from streptozotocin-diabetic rats maintained in poor or good control for 12 months (PC and GC respectively), or in PC for 6 months followed by 6 months of GC (Rev). The effect of direct inhibition of superoxide on prior insult was investigated by supplementing lipoic acid (LA) during their 6 months of GC (R + LA). Binding of TFAM with chaperones (heat shock proteins 70 and 60, Hsp70 and Hsp60 respectively) was quantified by coimmunoprecipitation. The key parameters and the number of mitochondria (by transmission electron microscopy and fluorescence microscopy) were confirmed in isolated retinal endothelial cells. RESULTS. Six months of GC in the rats in Rev group did not provide any benefit to diabetes-induced decreased mtDNA copy number, increased gene transcripts of PGC1, NRF1, and TFAM, and decreased mitochondrial TFAM. The binding of TFAM with the chaperones remained subnormal. Supplementation of LA (R + LA), however, had a significant beneficial effect on the impaired mitochondria biogenesis, and also on the continued progression of diabetic retinopathy. Similar results of reversal of high glucose insult were observed in isolated retinal endothelial cells. CONCLUSIONS. Dysregulated mitochondria biogenesis contributes to the metabolic memory, and supplementation of GC with therapies targeted in modulating mitochondria homeostasis has potential in helping diabetic patients retard progression of retinopathy. (Invest Ophthalmol Vis Sci. 2011;52:8791-8798) DOI:10.1167/iovs.11-8203