Department of Medicine, Queen's University, Kingston, Ontario, Canada.
Department of Medicine, Queen's Cardiopulmonary Unit (QCPU), Translational Institute of Medicine (TIME), Queen's University, Kingston, Ontario, Canada.
Compr Physiol. 2020 Mar 12;10(2):713-765. doi: 10.1002/cphy.c190027.
In lung vascular cells, mitochondria serve a canonical metabolic role, governing energy homeostasis. In addition, mitochondria exist in dynamic networks, which serve noncanonical functions, including regulation of redox signaling, cell cycle, apoptosis, and mitochondrial quality control. Mitochondria in pulmonary artery smooth muscle cells (PASMC) are oxygen sensors and initiate hypoxic pulmonary vasoconstriction. Acquired dysfunction of mitochondrial metabolism and dynamics contribute to a cancer-like phenotype in pulmonary arterial hypertension (PAH). Acquired mitochondrial abnormalities, such as increased pyruvate dehydrogenase kinase (PDK) and pyruvate kinase muscle isoform 2 (PKM2) expression, which increase uncoupled glycolysis (the Warburg phenomenon), are implicated in PAH. Warburg metabolism sustains energy homeostasis by the inhibition of oxidative metabolism that reduces mitochondrial apoptosis, allowing unchecked cell accumulation. Warburg metabolism is initiated by the induction of a pseudohypoxic state, in which DNA methyltransferase (DNMT)-mediated changes in redox signaling cause normoxic activation of HIF-1α and increase PDK expression. Furthermore, mitochondrial division is coordinated with nuclear division through a process called mitotic fission. Increased mitotic fission in PAH, driven by increased fission and reduced fusion favors rapid cell cycle progression and apoptosis resistance. Downregulation of the mitochondrial calcium uniporter complex (MCUC) occurs in PAH and is one potential unifying mechanism linking Warburg metabolism and mitochondrial fission. Mitochondrial metabolic and dynamic disorders combine to promote the hyperproliferative, apoptosis-resistant, phenotype in PAH PASMC, endothelial cells, and fibroblasts. Understanding the molecular mechanism regulating mitochondrial metabolism and dynamics has permitted identification of new biomarkers, nuclear and CT imaging modalities, and new therapeutic targets for PAH. © 2020 American Physiological Society. Compr Physiol 10:713-765, 2020.
在肺血管细胞中，线粒体起着典型的代谢作用，调节能量稳态。此外，线粒体存在于动态网络中，发挥非典型功能，包括调节氧化还原信号、细胞周期、细胞凋亡和线粒体质量控制。肺动脉平滑肌细胞 (PASMC) 中的线粒体是氧传感器，可引发低氧性肺血管收缩。线粒体代谢和动力学的获得性功能障碍导致肺动脉高压 (PAH) 中出现类似癌症的表型。获得性线粒体异常，如增加丙酮酸脱氢酶激酶 (PDK) 和丙酮酸激酶肌肉同工型 2 (PKM2) 的表达，增加解耦联糖酵解（Warburg 现象），与 PAH 有关。Warburg 代谢通过抑制氧化代谢来维持能量稳态，减少线粒体凋亡，从而允许不受控制的细胞积累。Warburg 代谢是通过诱导假性缺氧状态来启动的，在这种状态下，DNA 甲基转移酶 (DNMT) 介导的氧化还原信号变化导致 HIF-1α 的正常氧激活，并增加 PDK 的表达。此外，线粒体分裂通过称为有丝分裂分裂的过程与核分裂协调。PAH 中，分裂增加和融合减少导致有丝分裂分裂增加，有利于快速细胞周期进程和抗凋亡。PAH 中发生的线粒体钙单向转运体复合物 (MCUC) 下调是一种潜在的统一机制，将 Warburg 代谢和线粒体分裂联系起来。线粒体代谢和动态障碍的综合作用促进了 PAH PASMC、内皮细胞和成纤维细胞中的过度增殖、抗凋亡表型。了解调节线粒体代谢和动力学的分子机制，使人们能够识别新的生物标志物、核和 CT 成像方式以及 PAH 的新治疗靶点。© 2020 美国生理学会。综合生理学 10:713-765, 2020。
