线粒体自噬在心肌梗死中的作用及研究进展

张文静; 李晓峰; 孙明明; 彭沪

doi:10.16766/j.cnki.issn.1674-4152.002556

线粒体自噬在心肌梗死中的作用及研究进展

doi: 10.16766/j.cnki.issn.1674-4152.002556

张文静^{1, 2},
李晓峰²,
孙明明²,
彭沪^{1, 2, ,}

1.
南京医科大学附属上海十院临床医学院，上海 200072
2.
同济大学附属第十人民医院急诊科，上海 200072

基金项目:

国家自然科学基金项目 82000274

详细信息

通讯作者:
彭沪, E-mail: denkepeng@189.com

中图分类号: R542.22
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- 文章访问数: 1469
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- PDF下载量: 39
- 被引次数: 0
出版历程
- 收稿日期: 2022-02-08
- 网络出版日期: 2022-09-23

Research progress and function of mitophagy in myocardial infarction

ZHANG Wen-jing^{1, 2},
LI Xiao-feng²,
SUN Ming-ming²,
PENG Hu^{1, 2
, ,}

1.
Shanghai Tenth People's Hospital, School of Clinical Medicine, Nanjing Medical University, Shanghai 200072, China

摘要

摘要: 心肌梗死(MI)是指营养心脏的冠状动脉发生病变后，灌注血流急剧减少或中断，使心肌出现持久而严重的急性缺血缺氧导致的心肌缺血性坏死。心肌梗死患者心肌损伤的机制亟待明确，寻找干预靶点具有重要的临床价值。线粒体作为提供能量的细胞器，是心肌细胞内的主要能量来源，负责三磷酸腺苷(ATP)生成和能量代谢，线粒体完整性和功能的丧失是改变心脏结构和功能的重要病理因素，是心肌细胞不断收缩和舒张的关键保障。心肌梗死时线粒体功能异常是心肌损伤的重要机制，线粒体质量控制是指线粒体在生成与清除之间维持平衡，对维持细胞的生存及功能显得尤为重要。线粒体自噬与神经退行性疾病、心血管疾病、癌症等多种疾病相关。线粒体自噬是以损伤的线粒体作为自噬底物的一种选择性自噬，在心血管功能稳态的维持中具有重要作用。心肌缺血时，心肌细胞发生线粒体损伤，而线粒体自噬能通过促进降解和回收受损的线粒体以进行线粒体质量控制，进而保护缺血的心肌细胞。对于正常心肌细胞来说，足够的线粒体生成能够保证充足的能量供应；但当外界刺激导致线粒体损伤时，如果受损线粒体未及时清除造成堆积，会造成心肌细胞氧化应激损伤甚至引起细胞凋亡。线粒体自噬过程复杂，涉及诸多生理学及病理学过程，有多种物质如蛋白及RNA参与调控。本文将探讨线粒体自噬在心肌梗死中扮演的重要角色和相关机制。
- 线粒体自噬 /
- 心肌缺血性损伤 /
- 心肌梗死
Abstract: Myocardial infarction (MI) refers to myocardial ischemic necrosis caused by persistent and severe acute ischemia and hypoxia caused by acute reduction or interruption of perfusion blood flow after the coronary artery that nourishes the heart. The mechanism of myocardial injury in patients with MI needs to be clarified urgently. The research on the mechanism of MI and the search for intervention targets have important clinical value. The mitochondria, as organelles that provide energy, is the key organelles for the continuous contraction and relaxation of cardiac muscle cells. They are responsible for adenosine triphosphate generation and energy metabolism. The loss of mitochondrial integrity and function is a key pathological factor that changes the structure and function of the heart. Mitochondrial dysfunction during MI is an important mechanism of myocardial injury. Mitochondrial quality control refers to maintaining a balance between mitochondrial production and clearance, which is particularly essential for maintaining cell survival and function. Mitophagy is associated with various diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer. Mitophagy is a selective autophagy that uses damaged mitochondria as an autophagy substrate to maintain cardiovascular homeostasis. Mitophagy controls the quality of the mitochondria by promoting the degradation and recycling of damaged mitochondria and protects cardiomyocytes from ischemic injury. For normal cardiomyocytes, sufficient mitochondrial production could ensure sufficient energy supply. However, in the process of MI, mitochondrial damage occurs in cardiomyocytes and if the damaged mitochondria are not cleared in time, cardiomyocyte damage and even apoptosis could be induced. The process of mitophagy is complex, involving many physiological and pathological processes, and it is regulated by various substances, such as proteins and RNAs. In this article, the important roles and related mechanisms of mitophagy in MI are reviewed.
- Mitophagy /
- Myocardial ischemic injury /
- Myocardial infarction

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图 1 线粒体自噬途径

Figure 1. Mitophagy pathways

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参考文献(47)

[1]	BENJAMIN E J, BLAHA M J, CHIUVE S E, et al. Heart disease and stroke statistics-2017 update: A report from the american heart association[J]. Circulation, 2017, 135(10): e146-e603.
[2]	茅焕豪, 叶剑飞, 郑伟峰, 等. 左西孟旦联合冻干重组人脑利钠肽对缺血性心肌病患者心室重构改善作用的研究[J]. 中华全科医学, 2021, 19(11): 1861-1863, 1950. doi: 10.16766/j.cnki.issn.1674-4152.002186 MAO H H, YE J F, ZHENG W F, et al. Effect of levosimendan combined with lyophilized recombinant human brain natriuretic peptide on ventricular remodeling in patients with ischemic cardiomyopathy[J]. Chinese J Gen Pract, 2021, 19(11): 1861-1863, 1950. doi: 10.16766/j.cnki.issn.1674-4152.002186
[3]	BAUTERS C, DUBOIS E, POROUCHANI S, et al. Long-term prognostic impact of left ventricular remodeling after a first myocardial infarction in modern clinical practice[J]. PLoS One, 2017, 12(11): e0188884. DOI: 10.1371/journal.pone.0188884.
[4]	SUN M M, ZHANG W J, BI Y G, et al. NDP52 protects against myocardial infarction-provoked cardiac anomalies through promoting autophagosome-lysosome fusion via recruiting TBK1 and RAB7[J]. Antioxid Redox Signal, 2021. DOI: 10.1089/ars.2020.8253.
[5]	BUGGER H, PFEIL K. Mitochondrial ROS in myocardial ischemia reperfusion and remodeling[J]. Biochim Biophys Acta Mol Basis Dis, 2020, 1866(7): 165768. DOI: 10.1016/j.bbadis.2020.165768.
[6]	ZHANG Y, JIAO L, SUN L H, et al. LncRNA ZFAS1 as a SERCA2a inhibitor to cause intracellular Ca²⁺ overload and contractile dysfunction in a mouse model of myocardial infarction[J]. Circ Res, 2018, 122(10): 1354-1368. doi: 10.1161/CIRCRESAHA.117.312117
[7]	SUI X B, LIANG X, CHEN L X, et al. Bacterial xenophagy and its possible role in cancer: A potential antimicrobial strategy for cancer prevention and treatment[J]. Autophagy, 2017, 13(2): 237-247. doi: 10.1080/15548627.2016.1252890
[8]	MANCIAS J D, KIMMELMAN A C. Mechanisms of selective autophagy in normal physiology and cancer[J]. J Mol Biol, 2016, 428(9 Pt A): 1659-1680.
[9]	ZHANG Y M, WHALEY-CONNELL A T, SOWERS J R, et al. Autophagy as an emerging target in cardiorenal metabolic disease: From pathophysiology to management[J]. Pharmacol Ther, 2018. DOI: 10.1016/j.pharmthera.2018.06.004.
[10]	ZHOU H, WANG S Y, HU S Y, et al. ER-Mitochondria microdomains in cardiac ischemia-reperfusion injury: A fresh perspective[J]. Front Physiol, 2018. DOI: 10.3389/fphys.2018.00755.
[11]	JI C H, KWON Y T. Crosstalk and interplay between the ubiquitin-proteasome system and autophagy[J]. Mol Cells, 2017, 40(7): 441-449.
[12]	XU C L, CAO Y P, LIU R X, et al. Mitophagy-regulated mitochondrial health strongly protects the heart against cardiac dysfunction after acute myocardial infarction[J]. J Cell Mol Med, 2022, 26(4): 1315-1326. doi: 10.1111/jcmm.17190
[13]	QIU F, YUAN Y, LUO W, et al. Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy- and glycophagy-based energy metabolism[J]. Acta Pharmacol Sin, 2021. DOI: 10.1038/s41401-021-00763-9.
[14]	ZHANG W L, CHEN C Y, WANG J, et al. Mitophagy in cardiomyocytes and in platelets: A major mechanism of cardioprotection against Ischemia/Reperfusion injury[J]. Physiology(Bethesda), 2018, 33(2): 86-98.
[15]	YANG M J, LINN B S, ZHANG Y M, et al. Mitophagy and mitochondrial integrity in cardiac ischemia-reperfusion injury[J]. Biochim Biophys Acta Mol Basis Dis, 2019, 1865(9): 2293-2302. doi: 10.1016/j.bbadis.2019.05.007
[16]	SEKINE S, YOULE R J. PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol[J]. BMC Biol, 2018, 16(1): 2. doi: 10.1186/s12915-017-0470-7
[17]	XIONG W J, HUA J H, LIU Z H, et al. PTEN induced putative kinase 1(PINK1)alleviates angiotensin Ⅱ-induced cardiac injury by ameliorating mitochondrial dysfunction[J]. Int J Cardiol, 2018. DOI: 10.1016/j.ijcard.2018.03.054.
[18]	ZHANG R H, KRIGMAN J, LUO H K, et al. Mitophagy in cardiovascular homeostasis[J]. Mech Ageing Dev, 2020. DOI: 10.1016/j.mad.2020.111245.
[19]	MORALES P E, ARIAS-DURÁN C, ÁVALOS-GUAJARDO Y, et al. Emerging role of mitophagy in cardiovascular physiology and pathology[J]. Mol Aspects Med, 2020. DOI: 10.1016/j.mam.2019.09.006.
[20]	LUO H K, ZHANG R H, KRIGMAN J, et al. A healthy heart and a healthy brain: Looking at mitophagy[J]. Front Cell Dev Biol, 2020. DOI: 10.3389/fcell.2020.00294.
[21]	WANG B, NIE J L, WU L J, et al. AMPKα2 protects against the development of heart failure by enhancing mitophagy via PINK1 phosphorylation[J]. Circ Res, 2018, 122(5): 712-729. doi: 10.1161/CIRCRESAHA.117.312317
[22]	XIN T, LU C Z. Irisin activates Opa1-induced mitophagy to protect cardiomyocytes against apoptosis following myocardial infarction[J]. Aging(Albany NY), 2020, 12(5): 4474-4488.
[23]	FENG Y S, ZHAO J, HOU H F, et al. WDR26 promotes mitophagy of cardiomyocytes induced by hypoxia through Parkin translocation[J]. Acta Biochim Biophys Sin(Shanghai), 2016, 48(12): 1075-1084.
[24]	JI W Q, WEI S J, HAO P P, et al. Aldehyde dehydrogenase 2 has cardioprotective effects on myocardial Ischaemia/Reperfusion injury via suppressing mitophagy[J]. Front Pharmacol, 2016. DOI: 10.3389/fphar.2016.00101.
[25]	ZHOU H, ZHANG Y, HU S Y, et al. Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis[J]. J Pineal Res, 2017. DOI: 10.1111/jpi.12413.
[26]	WU J J, YANG Y L, GAO Y F, et al. Melatonin attenuates Anoxia/Reoxygenation injury by inhibiting excessive mitophagy through the MT2/SIRT3/FoxO3a signaling pathway in H9c2 cells[J]. Drug Des Devel Ther, 2020. DOI: 10.2147/DDDT.S248628.
[27]	WU S N, LU Q L, WANG Q L, et al. Binding of FUN14 Domain Containing 1 with inositol 1, 4, 5-trisphosphate receptor in mitochondria-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo[J]. Circulation, 2017, 136(23): 2248-2266. doi: 10.1161/CIRCULATIONAHA.117.030235
[28]	CHEN G, HAN Z, FENG D, et al. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy[J]. Molecular Cell, 2014, 54(3): 362-377. doi: 10.1016/j.molcel.2014.02.034
[29]	LU W, SUN J H, YOON J S, et al. Mitochondrial protein PGAM5 regulates mitophagic protection against cell necroptosis[J]. PLoS One, 2016. DOI: 10.1371/journal.pone.0147792.
[30]	YU W C, XU M, ZHANG T, et al. Mst1 promotes cardiac ischemia-reperfusion injury by inhibiting the ERK-CREB pathway and repressing FUNDC1-mediated mitophagy[J]. J Physiol Sci, 2019, 69(1): 113-127. doi: 10.1007/s12576-018-0627-3
[31]	ZHANG W L, SIRAJ S, ZHANG R, et al. Mitophagy receptor FUNDC1 regulates mitochondrial homeostasis and protects the heart from I/R injury[J]. Autophagy, 2017, 13(6): 1080-1081. doi: 10.1080/15548627.2017.1300224
[32]	ZHOU H, LI D D, ZHU P J, et al. Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways[J]. J Pineal Res, 2017. DOI: 10.1111/jpi.12438.
[33]	JIN Q H, LI R B, HU N, et al. DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways[J]. Redox Biol, 2018. DOI: 10.1016/j.redox.2017.11.004.
[34]	LEE T L, LEE M H, CHEN Y C, et al. Vitamin D attenuates Ischemia/Reperfusion-induced cardiac injury by reducing mitochondrial fission and mitophagy[J]. Front Pharmacol, 2020. DOI: 10.3389/fphar.2020.604700.
[35]	WHANG M I, TAVARES R M, BENJAMIN D I, et al. The ubiquitin binding protein TAX1BP1 mediates autophagasome induction and the metabolic transition of activated T cells[J]. Immunity, 2017, 46(3): 405-420. doi: 10.1016/j.immuni.2017.02.018
[36]	WANG Y, HAN Z H, XU Z J, et al. Protective effect of optic atrophy 1 on cardiomyocyte oxidative stress: roles of mitophagy, mitochondrial fission, and MAPK/ERK signaling[J]. Oxid Med Cell Longev, 2021. DOI: 10.1155/2021/3726885.
[37]	HOSHINO A, MITA Y, OKAWA Y, et al. Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart[J]. Nat Commun, 2013. DOI: 10.1038/ncomms3308.
[38]	TAHRIR F, KNEZEVIC T, GUPTA M, et al. Evidence for the role of BAG3 in mitochondrial quality control in cardiomyocytes[J]. J Cell Physiol, 2017, 232(4): 797-805. doi: 10.1002/jcp.25476
[39]	TAHRIR F G, KNEZEVIC T, GUPTA M K, et al. Evidence for the role of BAG3 in mitochondrial quality control in cardiomyocytes[J]. J Cell Physiol, 2017, 232(4): 797-805. doi: 10.1002/jcp.25476
[40]	TURKIEH A, CHARRIER H, DUBOIS-DERUY E, et al. Noncoding RNAs in cardiac autophagy following myocardial infarction[J]. Oxid Med Cell Longev, 2019. DOI: 10.1155/2019/8438650.
[41]	WANG L N, LI Q, DIAO J Y, et al. MiR-23a is involved in myocardial Ischemia/Reperfusion injury by directly targeting CX43 and regulating mitophagy[J]. Inflammation, 2021, 44(4): 1581-1591. doi: 10.1007/s10753-021-01443-w
[42]	WANG S H, ZHU X L, WANG F, et al. LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity[J]. Cell Death Dis, 2021, 12(6): 557. doi: 10.1038/s41419-021-03821-6
[43]	HU H, WU J W, LI D, et al. Knockdown of lncRNA MALAT1 attenuates acute myocardial infarction through miR-320-Pten axis[J]. Biomed Pharmacother, 2018. DOI: 10.1016/j.biopha.2018.06.122.
[44]	ZHAO Z H, HAO W, MENG Q T, et al. Long non-coding RNA MALAT1 functions as a mediator in cardioprotective effects of fentanyl in myocardial ischemia-reperfusion injury[J]. Cell Biol Int, 2017, 41(1): 62-70. doi: 10.1002/cbin.10701
[45]	ZHAO Y J, ZHOU L, LI H, et al. Nuclear-encoded lncRNA MALAT1 epigenetically controls metabolic reprogramming in HCC cells through the mitophagy pathway[J]. Mol Ther Nucleic Acids, 2021. DOI: 10.1016/j.omtn.2020.09.040.
[46]	SHAO G Y, ZHAO Z G, ZHAO W, et al. Long non-coding RNA MALAT1 activates autophagy and promotes cell proliferation by downregulating microRNA-204 expression in gastric cancer[J]. Oncol Lett, 2020, 19(1): 805-812.
[47]	ZHANG L, FANG Y, ZHAO X Y, et al. miR-204 silencing reduces mitochondrial autophagy and ROS production in a murine AD model via the TRPML1-activated STAT3 pathway[J]. Mol Ther Nucleic Acids, 2021. DOI: 10.1016/j.omtn.2021.02.010.