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Ravirajsinh Jadeja, Bhaumik Pandya, Malita Jones, Folami Lamoke Powell, Menaka Thounaojam, Manuela Bartoli, Pamela M Martin; Mechanisms of Mitochondrial Bioenergetic Crisis in Aging Retina. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4146.
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© ARVO (1962-2015); The Authors (2016-present)
Recent evidence suggests that in aging retinal pigment epithelium (RPE), altered mitochondrial function reduces ATP production creating a bioenergetic crisis. This in turn, increases cellular glycolytic metabolism and diminished glucose flow to photoreceptors precipitating photoreceptor death. However, the exact mechanism for the switch by RPE cells from oxidative phosphorylation to glycolysis under aging/disease conditions is not well characterized. In the present study, we focus on the role of pyruvate dehydrogenase (PDH), a gatekeeper mitochondrial enzyme that sits at the junction of two key metabolic pathways in mammalian cells, glycolysis and the TCA cycle.
Sodium iodate was used to induce oxidative stress in cultured primary human and mouse RPE cells and in the retinas of live mice. Mitochondria were isolated from intact mouse RPE tissue and from cultured primary mouse and human RPE cells to assay pyruvate dehydrogenase (PDH) activity. Oxidative phosphorylation and glycolysis were studied using a Seahorse Extracellular Flux Analyzer.
Knockdown of PDH in primary human RPE cells significantly reduced oxidative phosphorylation while glycolysis increased. Further, PDH knockdown was associated with loss of mitochondrial membrane potential and decreased density of healthy respiring mitochondria. In mouse and human RPE cells, time and dose dependent oxidative stress (induced by sodium iodate) decreased PDH activity. Similarly, in RPE tissue isolated from sodium iodate treated mice, PDH activity was significantly reduced. To confirm the direct role of PDH in the effects observed, human primary RPE were treated with pyruvate dehydrogenase kinase (PDK; a negative regulator of PDH); in this condition oxidative phosphorylation was significantly improved.
Our data confirms a prominent link between mitochondrial dysfunction and reduced PDH activity in RPE exposed to pro-oxidant conditions in vitro and in vivo. This study provides novel insight into the importance of PDH in regulating mitochondrial bioenergetics. In aging retina, increased oxidative stress could be an important factor for the dysfunction of PDH leading to bioenergetics crisis. Thus, testing and development of PDK inhibitors may be a broadly relevant therapeutic strategy to improve RPE functions in aging retina.
This is a 2020 ARVO Annual Meeting abstract.
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