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Ke Jiang, Anupam Mondal, Yogita Adlakha, Matthew Brooks, Linn Gieser, Jessica Gumerson, Kim Jung-Woong, Raul Covian Garcia, Anand Swaroop; Mitochondria Defects Constitute an Early Step in Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):431.
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© ARVO (1962-2015); The Authors (2016-present)
Mitochondria play an essential role in stringently regulating energy homeostasis, cell signaling and survival. Photoreceptors have high oxygen demand and are especially vulnerable to mitochondrial dysfunction, which has been implicated as a causal factor of neuronal cell death in retinal diseases. In this study, we analyzed mitochondria defects and expression profiles of mitochondrial genes/proteins at early stage of retinal degeneration, aiming to reveal the underlying factors that dictate the death fate of mutant photoreceptors.
As a model for photoreceptor degeneration, the well-established rd1 mouse was used in this study. We assayed morphological and physiological function of mitochondria and energy homeostasis in wild type and rd1 retinas. Furthermore, we used bioinformatics tools to evaluate and compare transcriptomic and proteomic profiles of photoreceptors/retinas in wild type and rd1 mice.
In rd1 mice, morphological defects in photoreceptor mitochondria was observed by transmission electron microscopy prior to the onset of degeneration when all mutant photoreceptors are still present. As an important parameter of OXPHOS activity, the basal oxygen consumption rate (OCR) and mitochondrial respiration reserve capacity (MRC) both deviated in rd1 retinas from that of wild type, prior to or at an early stage of degeneration. In addition, mit/nu DNA and NAD/NADH ratios were altered in rd1 retinas when compared to wild type. Lactate content, an indicator of glycolysis, did not show a significant change in rd1 retinas. Proteomic analysis of P6 rd1 and wild type retinas revealed specific reduction in several complex I subunits, followed by additional changes in complex III and V in P10 rd1 retinas. Transcriptome analyses of purified rod photoreceptors from rd1 retinas demonstrated significant and consistent changes as early as P2 (peak of rod birth), much before pathological phenotype is evident.
Our studies establish mitochondria defects as an early causal step in degenerative retinal diseases. Further analysis of RNAseq and proteomic data might suggest mechanistic connections between the early mitochondria defects to ultimate cell death.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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