Increasing Ca2+ in photoreceptor mitochondria alters metabolites, accelerates photoresponse recovery, and reveals adaptations to mitochondrial stress

• Published in: Cell death and differentiation Vol. 27; no. 3; pp. 1067 - 1085
• Main Authors: Hutto, Rachel A., Bisbach, Celia M., Abbas, Fatima, Brock, Daniel C., Cleghorn, Whitney M., Parker, Edward D., Bauer, Benjamin H., Ge, William, Vinberg, Frans, Hurley, James B., Brockerhoff, Susan E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2020; Nature Publishing Group
• Subjects: 101/58; 13; 13/1; 13/51; 14/19; 14/28; 14/35; 631/378; 631/45/269/1146; 631/45/320; 631/80; 64/116; 9/10; 96; 96/35; Adaptation; Apoptosis; Biochemistry; Biomedical and Life Sciences; Calcium (intracellular); Calcium (mitochondrial); Calcium homeostasis; Calcium influx; Calcium signalling; Cell Biology; Cell Cycle Analysis; Citric acid; Cones; Homeostasis; Intermediates; Life Sciences; Light effects; Metabolites; Mitochondria; Neurotransmission; Photoreceptors; Photoresponse; Phototransduction; Retinal degeneration; Stem Cells; Tricarboxylic acid cycle; Ultrastructure
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-019-0398-2

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.