Impaired Endoplasmic Reticulum (ER)-Mitochondrial Signaling in Ataxia-Telangiectasia Contributes to Mitochondrial Dysfunction

Abstract

Ataxia-telangiectasia (A-T) mutated (ATM) plays a central role in the response to DNA double strand breaks (DNA DSB) but there is increasing evidence that it has a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that A-T cells are also exquisitely sensitive to metabolic stress which can be explained by defective cross-talk between the endoplasmic reticulum (ER) and the mitochondrion through the mitochondrial–associated membrane (MAM). We showed that formation of a molecular bridge between the voltage-dependent calcium channel (VDAC1) and the inositol 1,4,5 trisphosphate receptor type 1 (IP3R1), mediated by the mitochondrial chaperone GRP75, is defective in A-T cells after nutrient stress. Tethering between these two organelles in response to stress, as determined by number of ER-mitochondrial contact sites, was reduced in A-T cells and consistent with this, Ca2+ release and transfer between ER and mitochondria was reduced dramatically compared to wild type 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 after glucose deprivation. Our findings reveal that ER- mitochondrial connectivity through IP3R1-GRP75-VDAC1, to maintain Ca2+ homeostasis, as well as an abnormality in mitochondrial fusion is defective in A-T cells in response to nutrient stress which can account for at least part of the mitochondrial dysfunction observed in A-T cells.