CERKL, a Retinal Dystrophy Gene, Regulates Mitochondrial Transport and Dynamics in Hippocampal Neurons

Abstract

Mutations in the Ceramide Kinase-Like (CERKL) gene cause retinal dystrophies, characterized by progressive degeneration of retinal neurons, which eventually lead to vision loss. Among other functions, CERKL is involved in the regulation of autophagy, mitochondrial dynamics, and metabolism in the retina. However, CERKL is nearly ubiquitously expressed, and it has been recently described to play a protective role against brain injury. Here we show that Cerkl is expressed in the hippocampus, and we use mouse hippocampal neurons to explore the impact of either overexpression or depletion of CERKL on mitochondrial trafficking and dynamics along axons. We describe that a pool of CERKL localizes at mitochondria in hippocampal axons. Importantly, the depletion of CERKL in the CerklKD/KO mouse model is associated with changes in the expression of fusion/fission molecular regulators, induces mitochondrial fragmentation, and impairs axonal mitochondrial trafficking. Our findings highlight the role of CERKL, a retinal dystrophy gene, in the regulation of mitochondrial health and homeostasis in central nervous system anatomic structures other than the retina.

Exacerbated response to oxidative stress in the Retinitis Pigmentosa Cerkl mouse model triggers retinal degeneration pathways upon acute light stress

“…The contribution of CERKL to mitochondrial dynamics and metabolism has already been assessed in previous work, in which CERKL / Cerkl downregulation resulted in smaller and dysfunctional mitochondria, whereas CERKL overexpression protected mitochondrial morphology and function from oxidative stress [ 15 , 18 , 19 ]. Here, we also describe alterations in the levels of different subunits of the ATP synthase upon Cerkl knockdown.…”

“…Mutations in CERKL cause two related but distinct inherited retinal dystrophies: Retinitis Pigmentosa and Cone-Rod Dystrophy, both of them causing irreversible attrition of photoreceptor cells, which eventually results in total blindness [ [9] , [10] , [11] , [12] ]. Previous studies have postulated CERKL as a resilience gene against oxidative stress in the retina by participating in autophagy [ [13] , [14] , [15] ], apoptosis inhibition [ 16 , 17 ], mitochondrial dynamics and function regulation [ 15 , 18 , 19 ], and stress granules formation [ 20 ]. On the latter, CERKL has been shown to interact with different proteins that compose mRNA stress-granules and P-bodies [ 20 ].…”