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eSymposia | Autophagy: Mechanisms and Disease


Unravelling CERKL role in regulating autophagy and mitochondrial function in the mammal retina


Oct 5, 2020 12:00am ‐ Oct 5, 2020 12:00am

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Unravelling CERKL role in regulating autophagy and mitochondrial function in the mammal retina Mirra S.(1,2), García-Arroyo R.(1), Gavaldà A.(3), Villaroya F.(3), Marfany G.(1,2,4) 1 Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, Spain 2 U718 CIBERER- ISCIII, Barcelona, Spain 3 Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain 4 IBUB-IRSJD, Barcelona, Spain The retina is the specialized region of the central nervous system that transduces light into neural signals. It is endowed with an active metabolism and displays a particular vulnerability to genetic and environmental factors causing stress and homeostatic imbalance. Autophagy is an intracellular mechanism essential for the adaptation to stress. In addition, mitochondria represent a bioenergetic hub coordinating stress response and cellular homeostasis. Therefore, both autophagy and mitochondrial metabolism and dynamics are relevant for retinal cell function. CERKL (ceramide kinase like) is a retinal degeneration (RD) gene, whose mutations cause Retinitis Pigmentosa in humans, a visual disorder characterized by photoreceptors neurodegeneration and progressive vision loss. Both in human and mouse, CERKL produces a wide range of isoforms whose subcellular localization and functional role may be different. Preliminary evidences indicate that CERKL protein is a sensor of photoreceptor stress by contributing to the formation of RNA stress granules. A complete knockout of the Cerkl locus is lethal at early embryonic stages in homozygosis. Consequently, we generated a double heterozygote knockdown/knockout model, CerklKD/KO in which the protein expression level is below 10% of that of the wild-type retina (B. Domènech et al., 2020). Here we describe a pool of CERKL isoforms localizing at mitochondria in mouse RGCs primary culture. In addition, we show that CerklKD/KO retinas are characterized by increased autophagy, alteration of the mitochondrial size and distribution and dysfunction in mitochondrial bioenergetics. Overall, our studies describe CERKL as a retinal gene involved in the regulation of autophagy and mitochondrial biology, adding knowledge to the picture of the multiple pathways controlling mitochondrial health in the mammal retina.

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