CERKL, a retinal dystrophy gene, regulates mitochondrial function and dynamics in the mammalian retina

Mirra, Serena; García-Arroyo, Rocío; Doménech, Elena; Gavaldà‐Navarro, Aleix; Herrera-Úbeda, Carlos; Oliva, Clara; Garcia‐Fernàndez, Jordi; Artuch, Rafael; Villarroya, Francesc; Marfany, Gemma

doi:10.1016/j.nbd.2021.105405

Cited by 18 publications

(27 citation statements)

References 57 publications

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“…This work showed that mitochondria in the RPE of the Cerkl KD/KO mouse (which expresses very low CERKL levels) show a significant decrease in length and area, in full agreement with previous results observed in photoreceptors and retinal ganglion cells [ 10 ], which reported an increase in mitochondrial fragmentation. To further dissect the contribution of CERKL to mitochondrial dynamics, particularly under oxidative stress conditions, we performed in vitro assays.…”

Section: Discussionsupporting

confidence: 92%

“…CERKL localizes at different cellular compartments, e.g., nuclei, Golgi apparatus, and mitochondria, among others, in both immortalized and primary cell lines [ 8 , 9 , 10 , 11 ]. However, little is known about the subcellular localization of CERKL in mammalian RPE.…”

Section: Resultsmentioning

confidence: 99%

“…A cerkl knock-out zebrafish model also shows defects in photoreceptor phagocytosis due to the dysfunction of RPE [ 26 ]. Although the precise function of CERKL is not yet fully determined, several reports associate CERKL with basic cell functions related to stress resilience, such as autophagy [ 9 ], stress granule production [ 11 ], and mitochondrial physiology and dynamics [ 10 ]. Within this context, we aimed to explore the alteration of RPE due to CERKL mutations both in vivo in a Cerkl mouse model and in vitro, using cultured cells to study the effect of CERKL overexpression and knock-down on the mitochondrial network organization.…”

Section: Discussionmentioning

confidence: 99%

“…Quantitative analyses of mitochondrial morphology and area in Transmission Electron Microscopy (TEM) microphotography 26,500× images and ARPE-19 cells were performed using an ImageJ software macro as described in [ 10 ]. Briefly, using ImageJ software, a threshold was established to distinguish mitochondria from the background.…”

Section: Methodsmentioning

confidence: 99%

“…This transcriptional complexity results in at least four CERKL isoforms displaying different protein domains [ 6 ]. CERKL isoforms have a dynamic subcellular localization and multiple functions: they act as a shuttle from the cytoplasm to the nucleus; are able to bind sphingolipids [ 7 ]; interact with antioxidant enzymes [ 8 ]; and regulate autophagy, and mitochondrial dynamics and metabolism [ 9 , 10 ]. Notably, CERKL has been also described as a RNA binding protein that localizes in polysomes, mRNA compact particles, stress granules (SG), and P-bodies under stress conditions [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of CERKL Protects Retinal Pigment Epithelium Mitochondria from Oxidative Stress Effects

et al. 2021

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The precise function of CERKL, a Retinitis Pigmentosa (RP) causative gene, is not yet fully understood. There is evidence that CERKL is involved in the regulation of autophagy, stress granules, and mitochondrial metabolism, and it is considered a gene that is resilient against oxidative stress in the retina. Mutations in most RP genes affect photoreceptors, but retinal pigment epithelium (RPE) cells may be also altered. Here, we aimed to analyze the effect of CERKL overexpression and depletion in vivo and in vitro, focusing on the state of the mitochondrial network under oxidative stress conditions. Our work indicates that the depletion of CERKL increases the vulnerability of RPE mitochondria, which show a shorter size and altered shape, particularly upon sodium arsenite treatment. CERKL-depleted cells have dysfunctional mitochondrial respiration particularly upon oxidative stress conditions. The overexpression of two human CERKL isoforms (558 aa and 419 aa), which display different protein domains, shows that a pool of CERKL localizes at mitochondria in RPE cells and that CERKL protects the mitochondrial network—both in size and shape—against oxidative stress. Our results support CERKL being a resilient gene that regulates the mitochondrial network in RPE as in retinal neurons and suggest that RPE cell alteration contributes to particular phenotypic traits in patients carrying CERKL mutations.

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Section: Discussionsupporting

confidence: 92%