Document Type

Article

Publication Date

8-21-2020

Comments

This article is the author’s final published version in iScience, Volume 23, Issue 8, August 2020, Article number 101370.

The published version is available at https://doi.org/10.1016/j.isci.2020.101370. Copyright © Roy Chowdhury et al.

Abstract

This study shows that multiple modes of mitochondrial stress generated by partial mtDNA depletion or cytochrome c oxidase disruption cause ryanodine receptor channel (RyR) dysregulation, which instigates the release of Ca2+ in the cytoplasm of C2C12 myoblasts and HCT116 carcinoma cells. We also observed a reciprocal downregulation of IP3R channel activity and reduced mitochondrial uptake of Ca2+. Ryanodine, an RyR antagonist, abrogated the mitochondrial stress-mediated increase in [Ca2+]c and the entire downstream signaling cascades of mitochondrial retrograde signaling. Interestingly, ryanodine also inhibited mitochondrial stress-induced invasive behavior in mtDNA-depleted C2C12 cells and HCT116 carcinoma cells. In addition, co-immunoprecipitation shows reduced FKBP12 protein binding to RyR channel proteins, suggesting the altered function of the Ca2+ channel. These results document how the endoplasmic reticulum-associated RyR channels, in combination with inhibition of the mitochondrial uniporter system, modulate cellular Ca2+ homeostasis and signaling under mitochondrial stress conditions.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

32738613

Language

English

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