#SeminarIRSJD · CERKL, a retinal dystrophy gene, regulates mitochondrial function and dynamics in both mammalian neuroretina and retinal pigment epithelium



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The retina is a highly active metabolic organ that displays a particular vulnerability to genetic and environmental factors causing stress and homeostatic imbalance. Mitochondria constitute a bioenergetic hub that coordinates stress response and cellular homeostasis, therefore structural and functional regulation of the mitochondrial dynamic network is essential for the mammalian retina. CERKL (ceramide kinase like) is a retinal degeneration gene whose mutations cause Retinitis Pigmentosa in humans, a rare disease characterized by photoreceptors neurodegeneration and progressive vision loss.

We aim to elucidate the precise cellular and molecular function of CERKL in mammalian retina and retinal pigment epithelium (RPE), by taking advantage of the knockdown/knockout (CerklKD/KO) in vivo model, generated by our group.

Our results showed that depletion of Cerkl causes increased autophagy, alteration of the mitochondrial size and distribution, and dysregulation of mitochondrial metabolism and other energy-related markers. Moreover, we found that under oxidative stress, CERKL overexpression protects RPE mitochondrial morphology, whereas depletion of CERKL causes mitochondrial fragmentation, respiratory dysfunction and polynucleation in RPE.

Overall, our results suggest that one of the physiological roles of CERKL is to protect the mitochondrial network in retinal cells, both neurons and epithelium, against the injury of light/oxidative stress. Importantly, we provide a solid link between inherited retinal disorders and the alteration of cell metabolism and homeostasis in the mammalian retina.

The characterization of CerklKD/KO retinas will contribute to the design of effective treatments for patients carrying CERKL mutations.