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

Cell Death Differ. 2020 Mar;27(3):1067-1085. doi: 10.1038/s41418-019-0398-2. Epub 2019 Aug 2.

Abstract

Photoreceptors are specialized neurons that rely on Ca2+ to regulate phototransduction and neurotransmission. Photoreceptor dysfunction and degeneration occur when intracellular Ca2+ homeostasis is disrupted. Ca2+ homeostasis is maintained partly by mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU), which can influence cytosolic Ca2+ 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 Ca2+ 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 Ca2+ and disruptions to mitochondrial ultrastructure until late adulthood. We exploited the survival of MCU overexpressing cones to additionally demonstrate that mitochondrial Ca2+ uptake alters the distributions of citric acid cycle intermediates and accelerates recovery kinetics of the cone response to light. Cones adapt to mitochondrial Ca2+ stress by decreasing MICU3, an enhancer of MCU-mediated Ca2+ uptake, and selectively transporting damaged mitochondria away from the ellipsoid toward the synapse. Our findings demonstrate how mitochondrial Ca2+ can influence physiological and metabolic processes in cones and highlight the remarkable ability of cone photoreceptors to adapt to mitochondrial stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological* / radiation effects
  • Animals
  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • Cytosol / metabolism
  • Disease Models, Animal
  • Isocitrate Dehydrogenase / metabolism
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Kinetics
  • Light Signal Transduction / radiation effects
  • Light*
  • Metabolome*
  • Mitochondria / metabolism*
  • Mitochondria / radiation effects
  • Mitochondria / ultrastructure
  • Models, Biological
  • Phenotype
  • Retinal Cone Photoreceptor Cells / metabolism*
  • Retinal Cone Photoreceptor Cells / radiation effects
  • Retinal Cone Photoreceptor Cells / ultrastructure
  • Stress, Physiological* / radiation effects
  • Zebrafish

Substances

  • Calcium Channels
  • mitochondrial calcium uniporter
  • Isocitrate Dehydrogenase
  • Ketoglutarate Dehydrogenase Complex
  • Calcium