线粒体代谢与干细胞的命运决定

doi:10.3877/cma.j.issn.2095-1221.2018.03.010

线粒体在真核细胞多种生物学过程中扮演重要角色，如能量产生、钙平衡、细胞内物质代谢、活性氧产生、细胞信号传导和凋亡等。线粒体的高度动态性，如生物发生、动态融合、分裂和退化等代谢特征与细胞种类、组织的需求密切相关。干细胞是一类具有自我更新和多向分化潜能的细胞。目前研究表明，线粒体的代谢与干细胞发育、命运决定紧密相关。本文综述干细胞干性维持及定向分化过程中，线粒体代谢改变与线粒体形态、结构和功能变化。

关键词: 线粒体, 代谢, 干细胞, 细胞命运, 决定

Mitochondria play fundamental roles in multiple processes in eukaryotic cells, including energy production, calcium homeostasis, intermediate metabolism, endogenous reactive oxygen species production, cell signaling, and apoptosis. In order to meet different demands of cell types and tissues, cells modulate mitochondrial function through biogenesis, degradation, dynamic fusion and fission events. Stem cells are defined by two key properties: self-renew and pluripotency. Studied show that the metabolism of mitochondria is closely related to the fate decision and the development of stem cells. Here, we review mitochondrial morphology, structure, function, and metabolic changes in the process of maintaining pluripotency of stem cells, and in the process of directed differentiation.

Key words: Mitochondria, Metabolism, Stem cell, Cell fate, Determination

图1 多能干细胞与成体细胞线粒体能量产生过程比较^[8]

表1 细胞类型与线粒体形态和代谢方式差异

细胞类型	线粒体形态	代谢方式	参考文献
胚胎干细胞	线粒体呈圆形，不成熟的形态，较低密度的基质，和极少量的嵴	主要依赖于糖酵解	[15,16]
多潜能干细胞	成熟度介于ESCs和已分化细胞之间，呈长圆形，少量嵴和致密基质	主要依赖于糖酵解	[17,18]
脂肪干细胞	线粒体呈长圆形，成熟度低，少量嵴和致密基质	主要依赖于糖酵解	[19]
肝实质细胞	长管状，成熟的线粒体形态，高电子密度的基质，相较于干细胞，有大量的嵴	氧化磷酸化	[20,21,22]

表1 细胞类型与线粒体形态和代谢方式差异

细胞类型	线粒体形态	代谢方式	参考文献
胚胎干细胞	线粒体呈圆形，不成熟的形态，较低密度的基质，和极少量的嵴	主要依赖于糖酵解	[15,16]
多潜能干细胞	成熟度介于ESCs和已分化细胞之间，呈长圆形，少量嵴和致密基质	主要依赖于糖酵解	[17,18]
脂肪干细胞	线粒体呈长圆形，成熟度低，少量嵴和致密基质	主要依赖于糖酵解	[19]
肝实质细胞	长管状，成熟的线粒体形态，高电子密度的基质，相较于干细胞，有大量的嵴	氧化磷酸化	[20,21,22]

14	Ezashi T, Das P, Roberts RM. Low O₂ tensions and the prevention of differentiation of hES cells[J]. Proc Natl Acad Sci U S A, 2005, 102(13):4783-4788.
15	Chung S, Arrell DK, Faustino RS, et al. Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation[J]. J Mol Cell Cardiol, 2010, 48(4):725-734.
16	Suhr ST, Chang AE, Tjong J, et al. Mitochondrial rejuvenation after induced pluripotency[J]. PLoS One, 2010, 5(11):e14095.
17	Chan HY, Keung W, Li RA, et al. Morphometric analysis of human embryonic stem Cell-Derived ventricular cardiomyocytes: determining the maturation state of a population by quantifying parameters in individual cells[J]. Stem Cells Int, 2015:586908.
18	Zhu L, Gomez-Duran A, Saretzki G, et al. The mitochondrial protein CHCHD2 primes the differentiation potential of human induced pluripotent stem cells to neuroectodermal lineages[J]. J Cell Biol, 2016, 215(2):187-202.
19	Marycz K, Michalak I, Kocherova I, et al. The cladophora glomerata enriched by biosorption process in Cr(Ⅲ) improves viability, and reduces oxidative stress and apoptosis in equine metabolic syndrome derived adipose mesenchymal stromal stem cells (ASCs) and their extracellular vesicles (MV's)[J]. Mar Drugs, 2017, 15(12).pii: E385.
20	Das S, Hajnóczky N, Antony AN, et al. Mitochondrial morphology and dynamics in hepatocytes from normal and ethanol-fed rats[J]. Pflugers Arch, 2012, 464(1):101-109.
21	Bahitham W, Liao XP, Peng F, et al. Mitochondriome and cholangiocellular carcinoma[J]. PLoS One, 2014, 9(8):e104694.
22	Rodriguez-Enriquez S, Kai Y, Maldonado EA, et al. Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes[J]. Autophagy, 2009, 5(8):1099-1106.
23	方海琴，李利忠，赵增明, 等. T-2毒素对小鼠胚胎干细胞线粒体功能的抑制作用[J]. 中国药理学与毒理学杂志, 2014, 28(3):415-420.
24	Huang P, Yc C, Chen LH, et al. PGC-1α mediates differentiation of mesenchymal stem cells to brown adipose cells[J]. J Atheroscler Thromb, 2011, 18(11):966-980.
25	Nazem S, Rabiee F, Ghaedi K, et al. Fndc5 knockdown induced suppression of mitochondrial integrity and significantly decreased cardiac differentiation of mouse embryonic stem cells[J]. J Cell Biochem, 2018, 119(6):4528-4539.
26	Zhang Y, Marsboom G, Toth PT, et al. Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells[J]. PLoS One, 2013, 8(10):e77077.
27	Zhang Y, Cui P, Li Y, et al. Mitochondrially produced ATP affects stem cell pluripotency via ActI6a-mediated histone acetylation[J]. FASEB J, 2018, 32(4):1891-1902.
28	Fortini P, Iorio E, Dogliotti E, et al. Coordinated metabolic changes and modulation of autophagy during myogenesis[J]. Front Physiol, 2016, 7:237.
29	Zhang J, Khvorostov I, Hong JS, et al. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells[J]. EMBO J. 2016, 35(8):899.
30	Pereira SL, Grãos M, Rodrigues AS, et al. Inhibition of mitochondrial complex Ⅲ blocks neuronal differentiation and maintains embryonic stem cell pluripotency[J]. PLoS One, 2013, 8(12):e82095.
31	Zhou W, Choi M, Margineantu D, et al. HIF1α induced Switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition[J]. EMBO J, 2012, 31(9):2103-2116.
32	Kaewsuwan S, Plubrukarn A, Utsintong M, et al. Interruptin B induces brown adipocyte differentiation and glucose consumption in adipose-derived stem cells[J]. Mol Med Rep, 2016, 13(3):2078-2086.
33	卢婉. MicroRNA-27通过靶向于抗增殖蛋白抑制脂肪干细胞分化及线粒体功能[D]. 南昌: 南昌大学医学院南昌大学, 2014.
34	Hom JR, Quintanilla RA, Hoffman DL, et al. The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation[J]. Dev Cell. 2011, 21(3):469-478.
35	Teslaa T, Teitell MA. Pluripotent stem cell energy metabolism: an update[J]. EMBO J, 2015, 34(2):138-153.
36	Otera H, Mihara K. Molecular mechanisms and physiologic functions of mitochondrial dynamics[J]. J Biochem, 2011, 149(3):241-251.
37	Westermann B. Mitochondrial fusion and fission in cell Life and death[J]. Nat Rev Mol Cell Biol, 2010, 11(12):872-884.
38	郝希纯，王东明. Drp1蛋白调节线粒体分裂机制及其在疾病中的作用[J]. 广东医学, 2011, 32(8):1066-1069.
39	Hoque A, Sivakumaran P, Bond ST, et al. Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells[J]. Cell Death Discov, 2018, 5:4:39.
40	Wang L, Ye XY, Zhao Q, et al. Drp1 is dispensable for mitochondria biogenesis in induction to pluripotency but required for differentiation of embryonic stem cells[J]. Stem Cells Dev, 2014, 23(20):2422-2434.
41	Son MY, Choi H, Han YM, et al. Unveiling the critical role of Rex1 in the regulation of human stem cell pluripotency[J]. Stem Cells, 2013, 31(11):2374-2387.
42	Joshi B, Ko D, Ordonez-Ercan D, et al. A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis[J]. Biochem Biophys Res Commun, 2003, 312(2):459-466.
43	Kowno M, Watanabe-Susaki K, Ishimine H, et al. Prohibitin 2 regulates the proliferation and lineage-specific differentiation of mouse embryonic stem cells in mitochondria[J]. PLoS One, 2014, 9(4):e81552.
1	李金泰，蓝升，刘毅. 3D打印干细胞技术用于组织器官重建的现状与思考[J]. 器官移植, 2017 (4):267-270.
2	Xu XL, Duan SL, Yi F, et al. Mitochondrial regulation in pluripotent stem cells[J]. Cell Metab, 2013, 18(3):325-332.
3	Mandal S, Lindgren AG, Srivastava AS, et al. Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells[J]. Stem Cells, 2011, 29(3):486-495.
4	Prigione A, Fauler B, Lurz R, et al. The Senescence-Related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells[J]. Stem Cells, 2010, 28(4):721-733.
5	Varum S, Rodrigues AS, Moura MB, et al. Energy metabolism in human pluripotent stem cells and their differentiated counterparts[J]. PLoS One, 2011, 6(6):e20914.
6	Prowse AB, Chong F, Elliott DA, et al. Analysis of mitochondrial function and localisation during human embryonic stem cell differentiation in vitro[J]. PLoS One, 2012, 7(12):e52214.
7	Lonergan T, Bavister B, Brenner C. Mitochondria in stem cells[J]. Mitochondrion, 2007, 7(5):289-296.
8	Holness MJ, Sugden MC. Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation[J]. Biochem Soc Trans, 2003, 31(6):1143-1151.
9	Wanet A, Arnould T, Najimi M, et al. Connecting mitochondria, metabolism, and stem cell fate[J]. Stem Cells Dev, 2015, 24(17):1957-1971.
44	Zhang XR, Zuo XX, Yang B, et al. MicroRNA directly enhances mitochondrial translation during muscle differentiation[J]. Cell, 2014, 158(3):607-619.
10	Hoque A, Sivakumaran P, Bond ST, et al. Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells[J]. Cell Death Discov, 2018, 4:39.
11	Pereira SL, Rodrigues AS, Sousa MI, et al. From gametogenesis and stem cells to cancer: common metabolic themes[J]. Hum Reprod Update, 2014, 20(6):924-943.
12	Wu JF, Niu J, Li X, et al. TGF-β1 induces senescence of bone marrow mesenchymal stem cells via increase of mitochondrial ROS production[J]. BMC Dev Biol, 2014, 14:21.
13	Heo JY, Jing K, Song KS, et al. Downregulation of APE1/Ref-1 is involved in the senescence of mesenchymal stem cells[J]. Stem Cells, 2009, 27(6):1455-1462.

[1]	刘婷婷, 林妍冰, 汪珊, 陈幕荣, 唐子鉴, 代东伶, 夏焙. 超声衰减参数成像评价儿童代谢相关脂肪性肝病的价值[J]. 中华医学超声杂志（电子版）, 2023, 20(08): 787-794.
[2]	伍秋苑, 陈佩贤, 邓裕华, 何添成, 周丹. 肠道微生物在乳腺癌中的研究进展[J]. 中华乳腺病杂志(电子版), 2023, 17(06): 362-365.
[3]	卫杨文祥, 黄浩然, 刘予豪, 陈镇秋, 王海彬, 周驰. 股骨头坏死细胞治疗的前景和挑战[J]. 中华关节外科杂志(电子版), 2023, 17(05): 694-700.
[4]	韩李念, 王君. 放射性皮肤损伤治疗的研究进展[J]. 中华损伤与修复杂志(电子版), 2023, 18(06): 533-537.
[5]	李婷, 张琳. 血清脂肪酸代谢物及维生素D水平与结直肠癌发生的关系研究[J]. 中华普外科手术学杂志(电子版), 2023, 17(06): 661-665.
[6]	陆闻青, 陈昕怡, 任雪飞. 遗传代谢病儿童肝移植受者术后生活质量调查研究[J]. 中华移植杂志(电子版), 2023, 17(05): 287-292.
[7]	何吉鑫, 杨燕妮, 王继伟, 李建国, 谢铭. 肠道菌群及肠道代谢产物参与慢性便秘发生机制的研究进展[J]. 中华结直肠疾病电子杂志, 2023, 12(06): 495-499.
[8]	潘春江, 李科, 李新楼, 杨博, 任雪玲. 高龄老人骨转换代谢标志物与肾功能的相关性研究[J]. 中华肾病研究电子杂志, 2023, 12(05): 260-264.
[9]	王旭, 师绍敏, 毛燕, 季上, 刘亚玲. 肝酶代谢与骨关节炎相关性的研究进展[J]. 中华老年骨科与康复电子杂志, 2023, 09(06): 379-384.
[10]	黄岩, 刘晓巍, 杨春玲, 兰烨. 急性胰腺炎合并糖尿病患者的临床特征及血糖代谢与病情严重度的相关性[J]. 中华消化病与影像杂志(电子版), 2023, 13(06): 439-442.
[11]	王磊, 李梦, 孙文利, 刘瑞, 王红春, 卢光泽, 赵颖, 郭进艳, 刘红星. 液相色谱质谱法对急性白血病患者血浆代谢组学的特征分析[J]. 中华临床医师杂志(电子版), 2023, 17(08): 850-857.
[12]	张大涯, 陈世锔, 陈润祥, 张晓冬, 李达, 白飞虎. 肠道微生物群对代谢相关脂肪性肝病发展的影响[J]. 中华临床医师杂志(电子版), 2023, 17(07): 828-833.
[13]	周加军, 余永武, 周涵, 刘勇, 张凌. 甲状旁腺切除对继发性甲状旁腺功能亢进患者骨密度及骨代谢的影响[J]. 中华临床医师杂志(电子版), 2023, 17(06): 706-710.
[14]	梁宇同, 丁旭, 马国慧, 黄艳红. 间充质干细胞在宫腔粘连治疗中的研究进展[J]. 中华临床医师杂志(电子版), 2023, 17(05): 596-599.
[15]	邱甜, 杨苗娟, 胡波, 郭毅, 何奕涛. 亚低温治疗脑梗死机制的研究进展[J]. 中华脑血管病杂志(电子版), 2023, 17(05): 518-521.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Mitochondrial metabolism and stem cells fate

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Mitochondrial metabolism and stem cells fate