ATM Loss Leads to Mitochondrial Dysfunction

The T-cell lymphomas that arise in ataxia-telangiectasia (A-T) patients are thought to be caused by impaired double-strand break (DSB) repair in the absence of ATM (ataxia-telangiectasia mutated), a nuclear protein that is a master regulator of the DNA damage response. However, some in vitro studies have suggested that a fraction of ATM is cytoplasmic and that it contributes to the maintenance of mitochondrial function. To establish whether ATM regulates mitochondrial homeostasis in vivo and evaluate the role of mitochondrial dysfunction in ATM-deficient tumors, Valentin-Vega and colleagues analyzed mitochondrial function in thymocytes of Atm-null mice. The mitochondria in Atm^−/− thymocytes exhibited altered morphology and decreased electron transport chain activity correlating with decreased cellular ATP and elevated levels of reactive oxygen species (ROS). ATM deficiency also led to an increase in mitochondrial mass, which was caused by decreased autophagic clearance of abnormal mitochondria, a process known as mitophagy. To determine whether abnormal autophagic processes contribute to the pathologies associated with A-T, the authors bred Atm-null mice to mice that were heterozygous for Beclin-1, a known regulator of autophagy. Surprisingly, Beclin-1 heterozygosity significantly delayed lymphomagenesis and increased survival in Atm-null mice, although it had no effect on the inherent DNA repair defect of Atm-deficient thymocytes. Instead, allelic loss of Beclin-1 significantly reversed the abnormalities in mitochondrial mass, electron transport chain activity, and ROS levels in Atm^−/− thymocytes. Finally, the authors showed that ATM is detectable in the mitochondria of normal human fibroblasts and is activated in response to mitochondrial damage without concomitant activation of DNA damage–induced ATM substrates. Collectively, these results establish an important cellular function for ATM independent of DSB repair and suggest that ATM-mediated tumor suppression may be partially attributable to regulation of mitochondrial homeostasis.

Valentin-Vega YA, MacLean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, et al. Mitochondrial dysfunction in ataxia telangiectasia. Blood 2011 Dec 5. [Epub ahead of print].

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