Increasing Ca2+ in photoreceptor mitochondria alters metabolites, accelerates photoresponse recovery, and reveals adaptations to mitochondrial stress
- Hutto, R.A., Bisbach, C.M., Abbas, F., Brock, D.C., Cleghorn, W.M., Parker, E.D., Bauer, B.H., Ge, W., Vinberg, F., Hurley, J.B., Brockerhoff, S.E.
- Cell death and differentiation 27(3): 1067-1085 (Journal)
- Registered Authors
- Abbas, Fatima, Brockerhoff, Susan, Hurley, James B.
- MeSH Terms
- Adaptation, Physiological*/radiation effects
- Calcium Channels/metabolism
- Disease Models, Animal
- Isocitrate Dehydrogenase/metabolism
- Ketoglutarate Dehydrogenase Complex/metabolism
- Light Signal Transduction/radiation effects
- Mitochondria/radiation effects
- Models, Biological
- Retinal Cone Photoreceptor Cells/metabolism*
- Retinal Cone Photoreceptor Cells/radiation effects
- Retinal Cone Photoreceptor Cells/ultrastructure
- Stress, Physiological*/radiation effects
- 31371786 Full text @ Cell Death Differ.
Hutto, R.A., Bisbach, C.M., Abbas, F., Brock, D.C., Cleghorn, W.M., Parker, E.D., Bauer, B.H., Ge, W., Vinberg, F., Hurley, J.B., Brockerhoff, S.E. (2019) Increasing Ca2+ in photoreceptor mitochondria alters metabolites, accelerates photoresponse recovery, and reveals adaptations to mitochondrial stress. Cell death and differentiation. 27(3):1067-1085.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes