OLA1 Phosphorylation Governs the Mitochondrial Bioenergetic Function of Pulmonary Vascular Cells.
OLA1 Phosphorylation Governs the Mitochondrial Bioenergetic Function of Pulmonary Vascular Cells.
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OLA1 磷酸化控制肺血管细胞的线粒体生物能功能。
DOI：
10.1165/rcmb.2022-0186oc
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发表时间：
2023
影响因子：
6.4
通讯作者：
Afolayan,AdeleyeJ
中科院分区：
文献类型：
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作者：
Sidlowski,Paul;Czerwinski,Amanda;Liu,Yong;Liu,Pengyuan;Teng,Ru-Jeng;Kumar,Suresh;Wells,Clive;PritchardJr,Kirkwood;Konduri,GirijaG;Afolayan,AdeleyeJ
线粒体功能和代谢稳态是心血管功能的组成部分，并影响血管细胞对应激的反应。然而，关于线粒体氧化还原控制机制和代谢调节如何在发育中的肺部相互作用知之甚少。本研究表明，人类OLA1 （obg样atp -1）通过激活细胞核中的代谢基因转录，将氧化还原信号与代谢反应途径结合在一起。OLA1在Ser232/Tyr236位点的磷酸化触发其从细胞质和线粒体转位到细胞核。随后，OLA1 Thr325位点的磷酸化有效地将其生化功能从ATPase转变为GTPase，促进了线粒体生物能量功能相关基因的表达。这一过程受到ERK1/2（细胞外调节激酶1和2）的调控，当应激减弱时，ERK1/2受到PP1A（蛋白磷酸酶1A）的抑制。ERK1或OLA1敲低突变为抗磷T325A突变体，阻断其核易位，损害核编码线粒体基因的表达，从而导致细胞能量消耗。此外，OLA1基因敲除小鼠的肺部线粒体更少，细胞ATP浓度更低，乳酸浓度更高。随之而来的线粒体代谢功能障碍导致肺血管细胞行为异常和明显的血管重塑。我们的研究结果表明，OLA1是线粒体逆行通信途径的重要组成部分，该途径将应激信号与细胞核中的代谢基因偶联。因此，控制细胞能量代谢的磷酸化依赖的核OLA1定位对心血管功能至关重要。
Mitochondrial function and metabolic homeostasis are integral to cardiovascular function and influence how vascular cells respond to stress. However, little is known regarding how mitochondrial redox control mechanisms and metabolic regulation interact in the developing lungs. Here we show that human OLA1 (Obg-like ATPase-1) couples redox signals to the metabolic response pathway by activating metabolic gene transcription in the nucleus. OLA1 phosphorylation at Ser232/Tyr236 triggers its translocation from the cytoplasm and mitochondria into the nucleus. Subsequent phosphorylation of OLA1 at Thr325 effectively changes its biochemical function from ATPase to GTPase, promoting the expression of genes involved in the mitochondrial bioenergetic function. This process is regulated by ERK1/2 (extracellular-regulated kinases 1 and 2), which were restrained by PP1A (protein phosphatase 1A) when stress abated. Knockdown of ERK1 or OLA1 mutated to a phosphoresistant T325A mutant blocked its nuclear translocation, compromised the expression of nuclear-encoded mitochondrial genes, and consequently led to cellular energy depletion. Moreover, the lungs of OLA1 knockout mice have fewer mitochondria, lower cellular ATP concentrations, and higher lactate concentrations. The ensuing mitochondrial metabolic dysfunction resulted in abnormal behaviors of pulmonary vascular cells and significant vascular remodeling. Our findings demonstrate that OLA1 is an important component of the mitochondrial retrograde communication pathways that couple stress signals with metabolic genes in the nucleus. Thus, phosphorylation-dependent nuclear OLA1 localization that governs cellular energy metabolism is critical to cardiovascular function.