Mitochondrial Calcium Uniporter (MCU) deficiency reveals an alternate path for Ca ²⁺ uptake in photoreceptor mitochondria

Abstract

Rods and cones use intracellular Ca ²⁺ to regulate many functions, including phototransduction and neurotransmission. The Mitochondrial Calcium Uniporter (MCU) complex is thought to be the primary pathway for Ca ²⁺ entry into mitochondria in eukaryotes. We investigate the hypothesis that mitochondrial Ca ²⁺ uptake via MCU influences phototransduction and energy metabolism in photoreceptors using a mcu ^-/- zebrafish and a rod photoreceptor-specific Mcu ^-/- mouse. Using genetically encoded Ca ²⁺ sensors to directly examine Ca ²⁺ uptake in zebrafish cone mitochondria, we found that loss of MCU reduces but does not eliminate mitochondrial Ca ²⁺ uptake. Loss of MCU does not lead to photoreceptor degeneration, mildly affects mitochondrial metabolism, and does not alter physiological responses to light, even in the absence of the Na ⁺/Ca ²⁺, K ⁺ exchanger. Our results reveal that MCU is dispensable for vertebrate photoreceptor function, consistent with its low expression and the presence of an alternative pathway for Ca ²⁺ uptake into photoreceptor mitochondria.