Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia

Abrey J Yeo; Kok L Chong; Magtouf Gatei; Dongxiu Zou; Romal Stewart; Sarah Withey; Ernst Wolvetang; Robert G Parton; Adam D Brown; Michael B Kastan; David Coman; Martin F Lavin

doi:10.1016/j.isci.2020.101972

Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia

iScience. 2020 Dec 23;24(1):101972. doi: 10.1016/j.isci.2020.101972. eCollection 2021 Jan 22.

Authors

Affiliations

¹ University of Queensland Centre for Clinical Research, The University of Queensland, Herston, Brisbane, Australia.
² QIMR Berghofer, Herston, Brisbane, Australia.
³ Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, Australia.
⁴ Institute for Molecular Bioscience and Centre for Microscopy and Microanalysis, The University of Queensland, St Lucia, Brisbane, Australia.
⁵ Duke University School of Medicine, Durham, NC, USA.
⁶ Queensland Children's Hospital, Brisbane, Australia.

Abstract

There is evidence that ATM mutated in ataxia-telangiectasia (A-T) plays a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that ATM-deficient cells are exquisitely sensitive to nutrient deprivation, which can be explained by defective cross talk between the endoplasmic reticulum (ER) and the mitochondrion. Tethering between these two organelles in response to stress was reduced in cells lacking ATM, and consistent with this, Ca²⁺ release and transfer between ER and mitochondria was reduced dramatically when compared with control cells. The impact of this on mitochondrial function was evident from an increase in oxygen consumption rates and a defect in mitophagy in ATM-deficient cells. Our findings reveal that ER-mitochondrial connectivity through IP3R1-GRP75-VDAC1, to maintain Ca²⁺ homeostasis, as well as an abnormality in mitochondrial fusion defective in response to nutrient stress, can account for at least part of the mitochondrial dysfunction observed in A-T cells.

Keywords: Cell Biology; Functional Aspects of Cell Biology; Organizational Aspects of Cell Biology.

Abstract

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