线粒体功能障碍在缺氧性肺动脉高压中的作用

doi:10.19586/j.2095-2341.2023.0072

生物技术进展 ›› 2023, Vol. 13 ›› Issue (6): 882-888.DOI: 10.19586/j.2095-2341.2023.0072

• 进展评述 • 上一篇

线粒体功能障碍在缺氧性肺动脉高压中的作用

潘舟(), 胡克()

武汉大学人民医院呼吸与危重症医学科，武汉 430060

收稿日期:2023-05-24 接受日期:2023-09-26 出版日期:2023-11-25 发布日期:2023-12-12
通讯作者: 胡克
作者简介:潘舟 E-mail: 810057469@qq.com；
基金资助:
国家自然科学基金面上项目(81970082)

The Role of Mitochondrial Dysfunction in Hypoxic Pulmonary Hypertension

Zhou PAN(), Ke HU()

Department of Respiratory and Critical Care Medicine，Renmin Hospital of Wuhan University，Wuhan 430060，China

Received:2023-05-24 Accepted:2023-09-26 Online:2023-11-25 Published:2023-12-12
Contact: Ke HU

摘要/Abstract

摘要：

在肺循环中，线粒体除了发挥典型的代谢作用外，还具有调节氧化还原信号、细胞周期、细胞凋亡以及线粒体质量控制等非典型功能。目前，对线粒体在肺循环中的非典型功能及其响应缺氧的作用机制的研究有限，需要对肺动脉高压的生物学标志物和治疗靶点有更多的了解。阐述了缺氧诱导的活性氧(reactive oxygen species，ROS)产生和细胞内钙离子浓度增加，以及缺氧对丙酮酸脱氢酶激酶和丙酮酸激酶M2型表达的影响，总结了线粒体融合和分裂在肺动脉平滑肌细胞增殖、抗凋亡表型等方面的作用，探讨了缺氧对线粒体活性、细胞行为以及线粒体功能障碍对肺动脉高压进展的影响。深入了解调控线粒体氧化信号、代谢和动态平衡的分子机制对研究和治疗肺动脉高压具有重要意义。

关键词: 线粒体功能障碍, 肺动脉高压, 缺氧, 活性氧

Abstract:

Mitochondria plays a pivotal role in the pulmonary circulation not only in typical metabolic processes but also in regulating oxidative-reduction signaling， cell cycle progression， cell apoptosis， and mitochondrial quality control， among other noncanonical functions. However， current understanding of these noncanonical mitochondrial functions in the pulmonary circulation and their response to hypoxia is limited. Therefore， there is a need for a deeper understanding of the biological markers and therapeutic targets associated with pulmonary arterial hypertension. This review elucidated the effects of hypoxia on mitochondrial activity and cellular behavior， including the induction of reactive oxygen species （ROS） generation and increased intracellular calcium levels. Furthermore， it highlighted the impact of hypoxia on the expression of pyruvate dehydrogenase kinase and pyruvate kinase M2， as well as the role of mitochondrial fusion and fission in pulmonary artery smooth muscle cell proliferation and resistance to apoptosis. Such investigations contributed to a comprehensive understanding of how hypoxia influences mitochondrial function and how mitochondrial dysfunction affects the progression of PAH. A thorough comprehension of the molecular mechanisms regulating mitochondrial oxidative signaling， metabolism， and dynamic equilibrium holds significant importance in the research and treatment of pulmonary arterial hypertension.

Key words: mitochondrial dysfunction, pulmonary arterial hypertension, hypoxia, reactive oxygen species

中图分类号:

Q591

潘舟, 胡克. 线粒体功能障碍在缺氧性肺动脉高压中的作用[J]. 生物技术进展, 2023, 13(6): 882-888.

Zhou PAN, Ke HU. The Role of Mitochondrial Dysfunction in Hypoxic Pulmonary Hypertension[J]. Current Biotechnology, 2023, 13(6): 882-888.

图/表 1

图1 缺氧性肺血管收缩的信号传递注：低氧增加了线粒体复合体Ⅲ产生的活性氧（ROS），ROS信号（超氧化物和H2O2）随后从膜间空间移动到细胞质，ROS可以抑制Kv通道，从而增加膜电位并打开电压依赖的Ca通道（CaL）。另外ROS还介导肌浆网上的三磷酸肌醇受体（IP3R）和RyR的激活，致Ca2+从肌浆网（sarcoplasmic reticulum,SR）释放，这两种途径都导致细胞质内Ca2+浓度增加，引起肺动脉平滑肌细胞收缩。线粒体ROS的增加和缺氧会抑制脯氨酰羟化酶（prolyl hydroxylase，PHD）的活性，使HIFα与HIFβ稳定结合，激活HIF靶基因。

Fig. 1 Signaling pathways in hypoxia-induced pulmonary vasoconstriction

参考文献 47

1	SIMONNEAU G, MONTANI D, CELERMAJER D S, et al.. Haemodynamic definitions and updated clinical classification of pulmonary hypertension[J/OL]. Eur. Respir. J., 2019, 53(1): 1801913[2023-10-19]. .
2	KLINGE C M. Estrogenic control of mitochondrial function[J/OL]. Redox Biol., 2020, 31: 101435[2023-10-19]. .
3	BRAND M D. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling[J]. Free Radic. Biol. Med., 2016, 100: 14-31.
4	NOLFI-DONEGAN D, BRAGANZA A, SHIVA S. Mitochondrial electron transport chain: oxidative phosphorylation, oxidant production, and methods of measurement[J/OL]. Redox Biol., 2020, 37: 101674[2023-10-19]. .
5	DUNHAM-SNARY K J, WU D, SYKES E A, et al.. Hypoxic pulmonary vasoconstriction: from molecular mechanisms to medicine[J]. Chest, 2017, 151(1): 181-192.
6	DUNHAM-SNARY K J， WU D， SYKES E A， et al.. Hypoxic pulmonary vasoconstriction： from molecular mechanisms to medicine［J］. Chest， 2017， 151（1）： 181-192I.
7	WARD J P, MCMURTRY I F. Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem[J]. Curr. Opin. Pharmacol., 2009, 9(3): 287-296.
8	WANG J, JUHASZOVA M, RUBIN L J, et al.. Hypoxia inhibits gene expression of voltage-gated K⁺ channel alpha subunits in pulmonary artery smooth muscle cells[J]. J. Clin. Investig., 1997, 100(9): 2347-2353.
9	ARCHER S L, HUANG J, HENRY T, et al.. A redox-based O₂ sensor in rat pulmonary vasculature[J]. Circ. Res., 1993, 73(6): 1100-1112.
10	SONG T, ZHENG Y M, WANG Y X. Cross talk between mitochondrial reactive oxygen species and sarcoplasmic reticulum calcium in pulmonary arterial smooth muscle cells[J]. Adv. Exp. Med. Biol., 2017, 967: 289-298.
11	GUZY R D, HOYOS B, ROBIN E, et al.. Mitochondrial complex Ⅲ is required for hypoxia-induced ROS production and cellular oxygen sensing[J]. Cell Metab., 2005, 1(6): 401-408.
12	WAYPA G B, MARKS J D, GUZY R, et al.. Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells[J]. Circ. Res., 2010, 106(3): 526-535.
13	BONNET S, MICHELAKIS E D, PORTER C J, et al.. An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension[J]. Circulation, 2006, 113(22): 2630-2641.
14	MARTINS PINTO M, PAUMARD P, BOUCHEZ C, et al.. The Warburg effect and mitochondrial oxidative phosphorylation: friends or foes?[J/OL]. Biochim. Biophys. Acta Bioenerg., 2023, 1864(1): 148931[2023-10-19]. .
15	CHETTIMADA S, GUPTE R, RAWAT D, et al.. Hypoxia-induced glucose-6-phosphate dehydrogenase overexpression and-activation in pulmonary artery smooth muscle cells: implication in pulmonary hypertension[J]. Am. J. Physiol. Lung Cell. Mol. Physiol., 2015, 308(3): 287-300.
16	蒋智渊,林葆菁,黄荣杰.线粒体分裂在肺动脉高压肺血管重构中的作用[J].中国病理生理杂志,2022,38(4):758-763.
17	PARK Y Y, NGUYEN O T, KANG H, et al.. MARCH5-mediated quality control on acetylated Mfn1 facilitates mitochondrial homeostasis and cell survival[J/OL]. Cell Death Dis., 2014, 5(4): e1172[2023-10-19]. .
18	LEBOUCHER G P, TSAI Y C, YANG M, et al.. Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis[J]. Mol. Cell, 2012, 47(4): 547-557.
19	WU H, CHEN Q. Hypoxia activation of mitophagy and its role in disease pathogenesis[J]. Antioxid. Redox Signal., 2015, 22(12): 1032-1046.
20	林晶晶,杨宇丰.线粒体自噬的调控机制及其在相关疾病中的作用[J].生物技术进展,2019,9(5):467-475.
21	马晨,宋怡菲,仪杨,等.氢气与线粒体作用关系的研究进展[J].生物技术进展,2023,13(3):366-374.
22	POST J M, HUME J R, ARCHER S L, et al.. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction[J]. Am. J. Physiol., 1992, 262(4): 882-890.
23	LIAO B, ZHENG Y M, YADAV V R, et al.. Hypoxia induces intracellular Ca²⁺ release by causing reactive oxygen species-mediated dissociation of FK506-binding protein 12.6 from ryanodine receptor 2 in pulmonary artery myocytes[J]. Antioxid. Redox Signal., 2011, 14(1): 37-47.
24	GONZÁLEZ-PACHECO F R, CARAMELO C, CASTILLA M A, et al.. Mechanism of vascular smooth muscle cells activation by hydrogen peroxide: role of phospholipase C gamma[J]. Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. Eur. Ren. Assoc., 2002, 17(3): 392-398.
25	DORJGOCHOO T, GAO Y T, CHOW W H, et al.. Major metabolite of F2-isoprostane in urine may be a more sensitive biomarker of oxidative stress than isoprostane itself[J]. Am. J. Clin. Nutr., 2012, 96(2): 405-414.
26	LÜNEBURG N, SIQUES P, BRITO J, et al.. Long-term chronic intermittent hypobaric hypoxia in rats causes an imbalance in the asymmetric dimethylarginine/nitric oxide pathway and ROS activity: a possible synergistic mechanism for altitude pulmonary hypertension?[J/OL]. Pulm. Med., 2016, 2016: 6578578[2023-10-19]. .
27	KISHIMOTO Y, KATO T, ITO M, et al.. Hydrogen ameliorates pulmonary hypertension in rats by anti-inflammatory and antioxidant effects[J]. J. Thorac. Cardiovasc. Surg., 2015, 150(3): 645-654.
28	VEITH C, SCHERMULY R T, BRANDES R P, et al.. Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension[J]. J. Physiol., 2016, 594(5): 1167-1177.
29	MARTÍNEZ-REYES I, CHANDEL N S. Mitochondrial TCA cycle metabolites control physiology and disease[J/OL]. Nat. Commun., 2020, 11(1): 102[2023-10-19]. .
30	TRUONG L, ZHENG Y M, WANG Y X. The potential important role of mitochondrial rieske iron-sulfur protein as a novel therapeutic target for pulmonary hypertension in chronic obstructive pulmonary disease[J/OL]. Biomedicines, 2022, 10(5): 957[2023-10-19]. .
31	WAYPA G B, MARKS J D, GUZY R D, et al.. Superoxide generated at mitochondrial complex Ⅲ triggers acute responses to hypoxia in the pulmonary circulation[J]. Am. J. Respir. Crit. Care Med., 2013, 187(4): 424-432.
32	ADESINA S E, KANG B Y, BIJLI K M, et al.. Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension[J]. Free. Radic. Biol. Med., 2015, 87: 36-47.
33	SIQUES P, BRITO J, PENA E. Reactive oxygen species and pulmonary vasculature during hypobaric hypoxia[J/OL]. Front. Physiol., 2018, 9: 865[2023-10-19]. .
34	JAMES M O, JAHN S C, ZHONG G, et al.. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1[J]. Pharmacol. Ther., 2017, 170: 166-180.
35	MICHELAKIS E D, MCMURTRY M S, WU X C, et al.. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels[J]. Circulation, 2002, 105(2): 244-250.
36	MICHELAKIS E D, GURTU V, WEBSTER L, et al.. Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients[J/OL]. Sci. Transl. Med., 2017, 9(413): eaao4583[2023-10-19]. .
37	SUTENDRA G, MICHELAKIS E D. The metabolic basis of pulmonary arterial hypertension[J]. Cell Metab., 2014, 19(4): 558-573.
38	DUMAS S J, BRU-MERCIER G, COURBOULIN A, et al.. NMDA-type glutamate receptor activation promotes vascular remodeling and pulmonary arterial hypertension[J]. Circulation, 2018, 137(22): 2371-2389.
39	MARSBOOM G, TOTH P T, RYAN J J, et al.. Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension[J]. Circ. Res., 2012, 110(11): 1484-1497.
40	RYAN J J, MARSBOOM G, FANG Y H, et al.. PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension[J]. Am. J. Respir. Crit. Care Med., 2013, 187(8): 865-878.
41	YE J X, WANG S S, GE M, et al.. Suppression of endothelial PGC-1α is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension[J]. Am. J. Physiol. Lung Cell. Mol. Physiol., 2016, 310(11): 1233-1242.
42	DIEBOLD I, HENNIGS J K, MIYAGAWA K, et al.. BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension[J]. Cell Metab., 2015, 21(4): 596-608.
43	LIU R, XU C, ZHANG W, et al.. FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia[J/OL]. Cell Death Dis., 2022, 13(7): 634[2023-10-19]. .
44	LIN M J, YANG X R, CAO Y N, et al.. Hydrogen peroxide-induced Ca²⁺ mobilization in pulmonary arterial smooth muscle cells[J]. Am. J. Physiol. Lung Cell. Mol. Physiol., 2007, 292(6): 1598-1608.
45	KINNEAR N P, WYATT C N, CLARK J H, et al.. Lysosomes co-localize with ryanodine receptor subtype 3 to form a trigger zone for calcium signalling by NAADP in rat pulmonary arterial smooth muscle[J]. Cell Calcium, 2008, 44(2): 190-201.
46	DROMPARIS P, PAULIN R, SUTENDRA G, et al.. Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension[J]. Circ. Res., 2013, 113(2): 126-136.
47	SUTENDRA G, DROMPARIS P, WRIGHT P, et al.. The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension[J/OL]. Sci. Transl. Med., 2011, 3(88): 88ra55[2023-10-19]. .

[1]	方学升, 包明威. 骨膜蛋白在心血管疾病中的研究进展[J]. 生物技术进展, 2023, 13(5): 725-729.
[2]	李世明, 张鹏, 赵鹏翔, 谢飞, 陈晓萍, 刘梦昱. 氧化应激与废用性肌萎缩研究进展[J]. 生物技术进展, 2023, 13(4): 524-533.
[3]	代地林, 吴园, 包明威. 单胺氧化酶A介导的活性氧簇在心血管疾病中的作用[J]. 生物技术进展, 2023, 13(4): 542-546.
[4]	赵忠朝,张玉秀，周正富，张维，陈明. 耐辐射异常球菌抗氧化保护机制的研究进展[J]. 生物技术进展, 2013, 3(2): 109-114.
[5]	张怡,路铁刚. 植物中的活性氧研究概述[J]. 生物技术进展, 2011, 1(4): 242-248.

线粒体功能障碍在缺氧性肺动脉高压中的作用

The Role of Mitochondrial Dysfunction in Hypoxic Pulmonary Hypertension

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

图/表 1

参考文献 47

相关文章 5

编辑推荐

Metrics

本文评价