Mitochondrial genome-encoded long noncoding RNA Cytochrome B and mitochondrial dysfunction in diabetic retinopathy

Antioxid Redox Signal. 2023 Jul 18. doi: 10.1089/ars.2023.0303. Online ahead of print.


Aim Mitochondrial dysfunction is closely associated with the development of diabetic complications. In diabetic retinopathy, electron transport chain is compromised and mtDNA is damaged, downregulating transcription of mtDNA-encoded cytochrome B (CYTB) and its antisense long noncoding RNA, LncCytB. Our goal was to investigate the role of LncCytB in the regulation of CYTB and mitochondrial function in diabetic retinopathy. Methods Using human retinal endothelial cells (HRECs), genetically manipulated for LncCytB (overexpression or silencing), the effect of high glucose (20mM D-glucose) on LncCytB-CYTB interactions (by Chromatin isolation by RNA Purification), CYTB gene expression (by qRT-PCR), 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. Results High glucose decreased LncCytB-CYTB interactions, and while LncCytB overexpression ameliorated glucose-induced decrease in CYTB gene transcripts, complex III activity and OCR and increase in mitochondrial ROS, LncCytB-siRNA further attenuated CYTB gene transcription, complex III activity and OCR. Similar decrease in LncCytB-CYTB interactions and CYTB transcription was observed in diabetic mice. Furthermore, protection of mitochondrial homeostasis by overexpressing superoxide dismutase or Sirtuin 1 in mice, ameliorated diabetes-induced decrease in LncCytB-CYTB interactions and CYTB gene transcripts, and also improved complex III activity and mitochondrial respiration. Innovation and Conclusion LncCytB downregulation in hyperglycemic milieu downregulates CYTB transcription, which inhibits complex III activity and compromises mitochondrial stability and oxygen consumption rate. Thus, preventing LncCytB downregulation in diabetes has potential of inhibiting the development of diabetic retinopathy, possibly via maintaining mitochondrial respiration.

PMID:37464864 | DOI:10.1089/ars.2023.0303