TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis

Buckley, N.; Craxton, A.; Sun, X.-M.; Panatta, E.; Pinon, L.; Llodra, J.; Morone, N.; Amelio, I.; Melino, G.; Martins, L. M.; MacFarlane, M.

doi:10.1101/2023.03.23.533672

bioRxiv · 10.1101/2023.03.23.533672

TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis

Buckley, N.·Craxton, A.·Sun, X.-M.·Panatta, E.·Pinon, L.·Llodra, J.·Morone, N.·Amelio, I.·Melino, G.·Martins, L. M.·MacFarlane, M.

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Abstract

Dysregulated mitochondrial fusion and fission has been implicated in the pathogenesis of numerous diseases. We have identified a novel function of the p53 family protein TAp73 in regulating mitochondrial dynamics. TAp73 regulates the expression of Optic atrophy 1, a protein responsible for controlling mitochondrial fusion, cristae biogenesis and electron transport chain function. Disruption of this axis results in a fragmented mitochondrial network and an impaired capacity for energy production via oxidative phosphorylation. Owing to the role of OPA1 in modulating cytochrome c release, TAp73-/- cells also display an increased sensitivity to apoptotic cell death, e.g., via BH3-mimetics. We also show that the TAp73/OPA1 axis has functional relevance in the upper airway, where TAp73 expression is essential for multiciliated cell differentiation and function. Consistently, ciliated epithelial cells of Trp73-/- (global p73 KO) mice display decreased expression of OPA1 and perturbations of the mitochondrial network, which may drive multiciliated cell loss. In support of this, Trp73 and OPA1 gene expression is decreased in COPD patients, a disease characterised by alterations in mitochondrial dynamics. We therefore highlight a potential mechanism involving the loss of p73 in COPD pathogenesis. This work also adds to the growing body of evidence for growth-promoting roles of TAp73 isoforms.

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Buckley, N., Craxton, A., Sun, X.-M., Panatta, E., Pinon, L., Llodra, J., Morone, N., Amelio, I., Melino, G., Martins, L. M., MacFarlane, M.. 2023-03-24. TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis. https://doi.org/10.1101/2023.03.23.533672

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