MAST1 is neuron-specific regulator of mitochondrial trafficking and abundance in human brain tissue
In human neurons, energy-demanding axonal and dendritic development requires sufficient mitochondrial distribution at distal locations, and the responsible mechanisms remain largely unknown. Here, we characterize rare de novo mutations in microtubule-associated serine/threonine kinase 1 (MAST1) in patients with multiple neurodevelopmental abnormalities, including microcephaly and thin corpus callosum. Experiments using induced pluripotent stem cell-derived telencephalic brain organoids and cortical neurons from patients and unaffected parents, as well as engineered lines demonstrate association of the MAST1 mutations with organoid growth deficits and impaired neurites. Mechanistically, the MAST1 mutations alter its interaction with mitochondria as well as mitochondrial trafficking and abundance, increasing the proportion of hyperactive mitochondria and reactive oxygen species accumulation. Exogenous wild-type MAST1 expression rescues neurite outgrowth in mutant neurons, as does prolonged treatment with creatine or N-acetyl-L-cysteine. This study identifies MAST1 as an important regulator of mitochondrial properties in human neurons and links microcephaly-associated MAST1 mutations to neuronal mitochondrial dysfunction, impaired neurites, and neuronal loss.