Lipid Transporter TMEM24/C2CD2L Plays Essential Roles in Retinal Photoreceptor Survival by Regulating Calcium Signaling and Synaptic Transmission.

Retinal neurotransmission is fundamental to vision, relying on the precise calcium-dependent release of glutamate at photoreceptor ribbon synapses. Disruptions in this pathway underlie multiple visual disorders in humans. TMEM24/C2CD2L, an SMP domain-containing phospholipid transporter enriched at endoplasmic reticulum (ER)-plasma membrane (PM) contact sites, regulates phosphoinositide homeostasis and calcium signaling. However, its role in the retina remains unknown. Here, we show that C2CD2L is predominantly expressed in retinal photoreceptors. Using a rod-specific conditional knockout mouse, we demonstrate that loss of C2CD2L impairs rod-mediated visual function, causes progressive outer retinal degeneration, induces reactive Müller glia activation, and triggers apoptotic photoreceptor death. Transcriptomic profiling of pre-degenerative retinas revealed significant downregulation of genes associated with voltage-gated calcium channel complexes, postsynaptic density membranes, and visual perception. These changes were accompanied by severe synaptic defects, including fewer RIBEYE- and Bassoon-positive puncta, reduced ribbon-bearing terminals, shortened synaptic ribbons, and decreased ribbon-tethered synaptic vesicles. Our findings establish C2CD2L as a critical regulator of rod photoreceptor synaptic integrity, calcium-channel-associated signaling, and retinal homeostasis.