MAST1 is neuron-specific regulator of mitochondrial trafficking and abundance in human brain tissue
- 1Neurobiology, Biomedical Engineering, Psychiatry departments, University of Utah, Cellular and Translational Research Core, Utah Clinical and Translational Scie
Abstract
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.
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BibTeX
@misc{ullah2026mast1,
title = {{MAST1 is neuron-specific regulator of mitochondrial trafficking and abundance in human brain tissue}},
author = {H. M. A. Ullah and K. L. NAPAN and I. KHIMACH and M. A. CUEVAS and Y. KIM and E. B. TAYLOR and M. A. SERRANO and A. S. RICCIARDULLI and S. ANDREADIS and Z. JIN and N. LOSURDO and A. HARRAHILL and C. MAGUIRE and J. J. KIM and A. BAJIC and W. SHEN and R. MAO and P. B.- TOYDEMIR and H. J. YOST and Y. IKEUCHI and J. RUTTER and L. D. BOTTO and J. C. CAREY and N. LINK and A. SHCHEGLOVITOV},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.764401},
url = {https://www.biorxiv.org/content/10.64898/2026.11.04.764401v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - MAST1 is neuron-specific regulator of mitochondrial trafficking and abundance in human brain tissue
AU - H. M. A. Ullah
AU - K. L. NAPAN
AU - I. KHIMACH
AU - M. A. CUEVAS
AU - Y. KIM
AU - E. B. TAYLOR
AU - M. A. SERRANO
AU - A. S. RICCIARDULLI
AU - S. ANDREADIS
AU - Z. JIN
AU - N. LOSURDO
AU - A. HARRAHILL
AU - C. MAGUIRE
AU - J. J. KIM
AU - A. BAJIC
AU - W. SHEN
AU - R. MAO
AU - P. B.- TOYDEMIR
AU - H. J. YOST
AU - Y. IKEUCHI
AU - J. RUTTER
AU - L. D. BOTTO
AU - J. C. CAREY
AU - N. LINK
AU - A. SHCHEGLOVITOV
PY - 2026
DA - 2026/11/04
PB - bioRxiv
DO - 10.64898/2026.11.04.764401
UR - https://www.biorxiv.org/content/10.64898/2026.11.04.764401v1
AB - 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.
ER -