Mitochondrial Genome-Encoded Long Noncoding RNA Cytochrome B and Mitochondrial Dysfunction in Diabetic Retinopathy.

Mitochondrial dysfunction is closely associated with the development of diabetic complications. In diabetic retinopathy, electron transport chain is compromised and mitochondrial DNA (mtDNA) is damaged, downregulating transcription of mtDNA-encoded cytochrome B () and its antisense long noncoding RNA, long noncoding RNA cytochrome B (Lnc). Our goal was to investigate the role of Lnc in the regulation of and mitochondrial function in diabetic retinopathy. Using human retinal endothelial cells, genetically manipulated for Lnc (overexpression or silencing), the effect of high glucose (20 m d-glucose) on Lnc- interactions (by chromatin isolation by RNA purification), gene expression (by real-time quantitative polymerase chain reaction), complex III activity, mitochondrial free radicals, and oxygen consumption rate (OCR, by Seahorse XF analyzer) was investigated. Key results were confirmed in the retinal microvessels from streptozotocin-induced diabetic mice. High glucose decreased Lnc interactions, and while Lnc overexpression ameliorated glucose-induced decrease in gene transcripts, complex III activity and OCR and increase in mitochondrial reactive oxygen species, Lnc further attenuated gene transcription, complex III activity, and OCR. Similar decrease in Lnc- interactions and transcription was observed in diabetic mice. Furthermore, maintenance of mitochondrial homeostasis by overexpressing superoxide dismutase or sirtuin 1 in mice ameliorated diabetes-induced decrease in Lnc- interactions and gene transcripts, and also improved complex III activity and mitochondrial respiration. Lnc downregulation in hyperglycemic milieu downregulates transcription, which inhibits complex III activity and compromises mitochondrial stability and OCR. Thus, preventing Lnc downregulation in diabetes has potential of inhibiting the development of diabetic retinopathy, possibly maintaining mitochondrial respiration. 39, 817-828.