Increasing Ca(2+) in photoreceptor mitochondria alters metabolites, accelerates photoresponse recovery, and reveals adaptations to mitochondrial stress

Photoreceptors are specialized neurons that rely on Ca(2+) to regulate phototransduction and neurotransmission. Photoreceptor dysfunction and degeneration occur when intracellular Ca(2+) homeostasis is disrupted. Ca(2+) homeostasis is maintained partly by mitochondrial Ca(2+) uptake through the mitochondrial Ca(2+) uniporter (MCU), which can influence cytosolic Ca(2+) signals, stimulate energy production, and trigger apoptosis. Here we discovered that zebrafish cone photoreceptors express unusually low levels of MCU. We expected that this would be important to prevent mitochondrial Ca(2+) overload and consequent cone degeneration. To test this hypothesis, we generated a cone-specific model of MCU overexpression. Surprisingly, we found that cones tolerate MCU overexpression, surviving elevated mitochondrial Ca(2+) and disruptions to mitochondrial ultrastructure until late adulthood. We exploited the survival of MCU overexpressing cones to additionally demonstrate that mitochondrial Ca(2+) uptake alters the distributions of citric acid cycle intermediates and accelerates recovery kinetics of the cone response to light. Cones adapt to mitochondrial Ca(2+) stress by decreasing MICU3, an enhancer of MCU-mediated Ca(2+) uptake, and selectively transporting damaged mitochondria away from the ellipsoid toward the synapse. Our findings demonstrate how mitochondrial Ca(2+) can influence physiological and metabolic processes in cones and highlight the remarkable ability of cone photoreceptors to adapt to mitochondrial stress.