TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis
TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis
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DOI：
10.1101/2023.03.23.533672
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发表时间：
2023-03
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通讯作者：
Niall Buckley;A. Craxton;Xiao-Ming Sun;Emanuele Panatta;L. Piñón;Jaime Llodrá;N. Morone;I. Amelio;G. Melino;L. Martins;M. MacFarlane
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作者：
Niall Buckley;A. Craxton;Xiao-Ming Sun;Emanuele Panatta;L. Piñón;Jaime Llodrá;N. Morone;I. Amelio;G. Melino;L. Martins;M. MacFarlane
线粒体融合和分裂失调与许多疾病的发病机制有关。我们已经确定了一个新的功能的p53家族蛋白TAp 73在调节线粒体动力学。TAp 73调节视神经萎缩1的表达，视神经萎缩1是一种负责控制线粒体融合、嵴生物发生和电子传递链功能的蛋白质。该轴的破坏导致线粒体网络碎片化和通过氧化磷酸化产生能量的能力受损。由于OPA 1在调节细胞色素c释放中的作用，TAp 73-/-细胞也显示出对凋亡性细胞死亡的敏感性增加，例如，通过BH 3-模拟物。我们还表明，TAp 73/OPA 1轴在上气道中具有功能相关性，其中TAp 73表达对于多纤毛细胞分化和功能至关重要。一致地，Trp 73-/-（全局p73 KO）小鼠的纤毛上皮细胞显示OPA 1表达降低和线粒体网络的扰动，这可能驱动多纤毛细胞损失。为了支持这一点，Trp 73和OPA 1基因表达在COPD患者中降低，COPD患者是一种以线粒体动力学改变为特征的疾病。因此，我们强调了一个潜在的机制，涉及的损失p73在COPD发病机制。这项工作也增加了越来越多的TAp 73同种型促进生长作用的证据。
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.