Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia

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, Ca 2+ 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 Ca 2+ 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. (© 2020 The Authors.)eCollection. Cited Medium: Internet. NLM ISO Abbr: iScience. PubMed Central ID: PMC7788243. Linked References: Radiat Res. 2018 Aug;190(2):204-215. (PMID: 29863983); Nat Cell Biol. 2012 Mar 25;14(5):535-41. (PMID: 22446738); Nature. 2013 Mar 21;495(7441):389-93. (PMID: 23455425); Biomolecules. 2015 Oct 23;5(4):2877-902. (PMID: 26512707); J Cell Biol. 2006 Dec 18;175(6):901-11. (PMID: 17178908); Acta Biochim Biophys Sin (Shanghai). 2008 Apr;40(4):339-48. (PMID: 18401532); Stroke. 2002 Oct;33(10):2471-7. (PMID: 12364740); Adv Sci (Weinh). 2020 Feb 14;7(6):1903616. (PMID: 32195105); Nat Cell Biol. 2015 Oct;17(10):1259-1269. (PMID: 26344566); Mol Med Rep. 2012 Dec;6(6):1423-7. 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