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

Cell Death and Differentiation
R. A. HuttoSusan E Brockerhoff

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 transportin...Continue Reading

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Citations

May 23, 2020·Human Genetics·Gao-Hui ZhouZi-Bing Jin
Aug 21, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yunzhen LiVincent Torre
Jan 14, 2021·Biomolecules·Nicole C L NoelW Ted Allison
Nov 5, 2020·Proceedings of the National Academy of Sciences of the United States of America·Michelle M GiarmarcoSusan E Brockerhoff
Feb 26, 2021·Communications Biology·Warren W PanCagri G Besirli
Apr 4, 2021·Journal of Developmental Biology·Natalia JaroszynskaMariya Moosajee
Jun 9, 2021·Annual Review of Vision Science·James B Hurley
Nov 20, 2021·Investigative Ophthalmology & Visual Science·Kristine A TsantilasJames B Hurley

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Methods Mentioned

BETA
transgenic
electron microscopy
Protein Assay

Key Resources (RRID) Mentioned

AB_2084810
AB_301432
AB_10866116
AB_11205754
AB_2576208
AB_2714032
SCR_014579
SCR_013673
SCR_014215
SCR_008954

Software Mentioned

TrakEM2
NormFinder
SutterPatch
Olympus
ImageJ Grid / Collection
Leica LAS - X
GraphPad
Fiji
geNorm
FluoView FV10 - ASW

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