Mitochondrial Ca²⁺influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

Abstract

9Mitochondrial Ca 2+ regulates key cellular processes including cytosolic Ca 2+ signals, 10 energy production, and susceptibility to apoptosis. Photoreceptors are specialized 11 neurons that have extraordinarily high energy demands and rely on cytosolic Ca 2+ 12 signals for light adaptation and neurotransmission. Here we show that unlike other 13 neurons zebrafish cone photoreceptors express low levels of the mitochondrial Ca 2+ 14 uniporter (MCU), the channel that allows mitochondrial Ca 2+ entry. To determine why 15 MCU expression is kept low, we overexpressed MCU specifically in cones. This 16 increases mitochondrial [Ca 2+ ], causes faster cytosolic Ca 2+ clearance, and accelerates 17 photoresponse recovery. Moreover, flux through the citric acid cycle increases despite 18 dramatic changes in mitochondrial ultrastructure and localization. Remarkably, cones 19 survive this ongoing stress until late adulthood. Our findings demonstrate the 20 importance of tuning mitochondrial Ca 2+ influx to modulate physiological and metabolic 21 processes and reveal a novel directed movement of abnormal mitochondria in 22 photoreceptors. 23Mitochondrial Ca 2+ uptake is also involved in energetic output (Glancy and Balaban, 57 2012). Ca 2+ can regulate the activity of mitochondrial enzymes including pyruvate 58 dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase 59