Ataxia Telangiectasia patient-derived neuronal and brain organoid models reveal mitochondrial dysfunction and oxidative stress

Ataxia Telangiectasia (AT) is a rare genetic disorder caused by mutations in the ATM gene and is characterized by oxidative stress, premature ageing, and progressive neurodegeneration of the cerebellum. The molecular mechanisms driving the neurological defects AT remain unclear, mainly due to lack of human neuronal models. Here, we use AT patient-derived pluripotent stem cells (iPSCs) and iPSC-derived neurons and brain organoids to comprehensively explore mitochondrial dysfunction, oxidative stress, and senescence phenotypes. We identified mislocalisation of mitochondria, a prevailing reduction in mitochondrial membrane potential, and increased oxidative stress in AT patient-derived iPSC and neuronal cultures that was restored by ATM gene correction. Cortical brain organoids from AT patients also display extensive oxidative stress, increased levels of senescence, and impaired neuronal function that could be counteracted with antioxidant treatment. Transcriptomic analysis identified disruptions in regulatory networks related to mitochondrial function and maintenance, including alterations in the PARP/SIRT signalling axis and dysregulation of key mitophagy and mitochondrial fission-fusion processes. Our study reveals that progressive mitochondrial dysfunction and aberrant ROS production are hallmarks of AT, and lead us to conclude that ATM is a master regulator of mitochondrial homeostasis.