Fishburn, J.;Zhao, H.;Fosselman, W.;Flores, J.;Wong, M.;Singh, T.;Chen, S.;Barlow, J.

Ataxia with oculomotor apraxia type 2 (AOA2) is a rare neurodegenerative disease caused by loss-of-function mutations in Senataxin, which encodes an RNA:DNA helicase. Many studies on Senataxin loss focus on its putative roles in regulating transcription and RNA transcript localization. However, several phenotypes remain underexplored, including metabolic dysregulation associated with ataxias. Using Senataxin-deficient mouse cells, we observed increased nuclear and genomic instability, as well as innate immune activation via the cGAS-STING axis. We also observed elevated ROS levels, decreased mitochondrial function, and hyperfused mitochondria. Importantly, mitochondrial dysfunction depends on cGAS/STING activity, indicating that the two phenotypes are functionally connected. Senataxin-deficient mice and AOA2 patient cells similarly exhibit spontaneous innate immune activation, and AOA2 patient cells also show decreased mitochondrial function. Our work identifies a previously unseen phenotype for AOA2 in which loss of Senataxin results in mitochondrial dysfunction promoted by cGAS and STING. Summary This study demonstrates a previously unidentified phenotype in AOA2 and Senataxin research in which cGAS-STING promotes mitochondrial dysregulation in Setx -/- MEFs. Further, these innate immune activation and mitochondrial dysregulated phenotypes are recapitulated in AOA2 patient cells.