线粒体融合、分裂及其相关疾病的研究进展

doi:10.16431/j.cnki.1671-7236.2017.06.001

摘要/Abstract

摘要：

近年来，有关线粒体融合和分裂机制的相关研究越来越多。线粒体是所有真核生物都不可或缺的双层膜细胞器，大多数细胞中线粒体是高度动态的，且通过不断地融合、分裂来维持动态平衡。线粒体外膜与内膜的融合分别由Mfn1、Mfn2与多种形式的OPA1调控；DRP1介导外膜分裂，内膜的分裂可能是由S-OPA1和MTP18介导。多种客观因素通过影响融合或分裂的程度，进而影响线粒体的融合与分裂，提高线粒体融合程度或降低线粒体分裂程度都将导致在细胞内形成个体大、数量少的线粒体；反之，将出现个体小、数量多的线粒体。可以据此特性间接检测某项影响线粒体形态学变化的因素，了解线粒体动态变化所涉及的蛋白，以及影响线粒体形态学的重要外部因素、线粒体相关疾病的发病原因。因此，作者在总结前人研究成果的基础上，针对线粒体融合与分裂、参与线粒体融合与分裂的相关蛋白及线粒体融合、分裂与疾病的发生进行了综述。

关键词: 线粒体; 形态学; 蛋白质; 动态变化; 疾病发生

Abstract:

In recent years, more and more studies on mitochondrial fusion and fragmentation mechanisms have been conducted, mitochondria are double-membrane organelles possessed by all eukaryotic organisms. In most cells, mitochondria are highly dynamic and maintain their homeostasis by continually fusing and dividing.Mitochondrial outer membrane and endometrial fusion were regulated, respectively by Mfn1, Mfn2 and a variety of forms of OPA1;DRP1 mediated epineurial division,at present the mechanism of endometrial fission is still unclear,may be mediated by S-OPA1 and MTP18. Research shows that a variety of objective factors through the impact of the degree of integration or division,thus affecting the mitochondrial fusion and fission,increased mitochondrial fusion or decreased mitochondrial fission will result in the cell into individual large, small number of mitochondria;On the contrary,will lead to mitochondria appear individual small, large number. In the future research process, this feature can be used to detect indirectly a change in mitochondrial morphology factors. On the basis of summarizing the results of previous studies, in the present review, we focus on the mitochondrial fusion and fission, some related proteins involved in mitochondrial fusion and fission, as well as the occurrence of mitochondrial disease.

Key words: mitochondria; morphology; protein; dynamic change; disease occurrence

中图分类号:

Q244

韩雨轩, 庞欣茹, 吴月红, 赵洪新. 线粒体融合、分裂及其相关疾病的研究进展[J]. 《中国畜牧兽医》, 2017, 44(6): 1571-1579.

HAN Yu-xuan, PANG Xin-ru, WU Yue-hong, ZHAO Hong-xin. Research Progress on the Mitochondrial Fusion, Fission and Their Effects on Disease[J]. , 2017, 44(6): 1571-1579.

参考文献

[1] Henze K, Martin W. Evolutionary biology: Essence of mitochondria[J]. Nature, 2003, 426(6963): 127-128.
[2] Da Silva A F, Mariotti F R, Máximo V, et al. Mitochondria dynamism: Of shape, transport and cell migration[J]. Cellular and Molecular Life Sciences, 2014, 71(12): 2313-2324.
[3] Vafai S B, Mootha V K. Mitochondrial disorders as windows into an ancient organelle[J]. Nature, 2012, 491(7424): 374-383.
[4] Wai T, Langer T. Mitochondrial dynamics and metabolic regulation[J]. Trends in Endocrinology & Metabolism, 2016, 27(2): 105-117.
[5] Youle R J, van Der Bliek A M. Mitochondrial fission, fusion, and stress[J]. Science, 2012, 337(6098): 1062-1065.
[6] Gardner A, Boles R G. Is a "mitochondrial psychiatry" in the future? A review[J]. Current Psychiatry Reviews, 2005, 1(3): 255-271.
[7] Lesnefsky E J, Moghaddas S, Tandler B, et al. Mitochondrial dysfunction in cardiac disease: Ischemia-reperfusion, aging, and heart failure[J]. Journal of Molecular and Cellular Cardiology, 2001, 33(6): 1065-1089.
[8] Dorn G W, Vega R B, Kelly D P. Mitochondrial biogenesis and dynamics in the developing and diseased heart[J]. Genes & Development, 2015, 29(19): 1981-1991.
[9] Goh S, Dong Z, Zhang Y, et al. Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: Evidence from brain imaging[J]. JAMA Psychiatry, 2014, 71(6): 665-671.
[10] Lackner L L. Shaping the dynamic mitochondrial network[J]. BMC Biology, 2014, 12(1): 35.
[11] Nunnari J, Suomalainen A. Mitochondria: In sickness and in health[J]. Cell, 2012, 148(6): 1145-1159.
[12] Lackner L L. Determining the shape and cellular distribution of mitochondria:The integration of multiple activities[J]. Current Opinion in Cell Biology, 2013, 25(4): 471-476.
[13] Hoppins S, Lackner L, Nunnari J. The machines that divide and fuse mitochondria[J]. Annu Rev Biochem, 2007, 76: 751-780.
[14] Nunnari J, Marshall W F, Straight A, et al. Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA[J]. Molecular Biology of the Cell, 1997, 8(7): 1233-1242.
[15] Twig G, Hyde B, Shirihai O S. Mitochondrial fusion, fission and autophagy as a quality control axis: The bioenergeticview[J]. Biochimicaet Biophysica Acta (BBA)-Bioenergetics, 2008, 1777(9): 1092-1097.
[16] Twig G, Elorza A, Molina A J A, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy[J]. The EMBO Journal, 2008, 27(2): 433-446.
[17] Mishra P, Chan D C. Mitochondrial dynamics and inheritance during cell division, development and disease[J]. Nature Reviews Molecular Cell Biology, 2014, 15(10): 634-646.
[18] Chen H, Detmer S A, Ewald A J, et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development[J]. The Journal of Cell Biology, 2003, 160(2): 189-200.
[19] Anand R, Wai T, Baker M J, et al. The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission[J]. The Journal of Cell Biology, 2014, 204(6): 919-929.
[20] Ishihara N, Fujita Y, Oka T, et al. Regulation of mitochondrial morphology through proteolytic cleavage of OPA1[J]. The EMBO Journal, 2006, 25(13): 2966-2977.
[21] Anand R, Langer T, Baker M J. Proteolytic control of mitochondrial function and morphogenesis[J]. Biochimica Et Biophysica Acta (BBA)-Molecular Cell Research, 2013, 1833(1): 195-204.
[22] Civiletto G, Varanita T, Cerutti R, et al. OPA1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models[J]. Cell Metabolism, 2015, 21(6): 845-854.
[23] Palmer C S, Elgass K D, Parton R G, et al. Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in DRP1 recruitment and are specific for mitochondrial fission[J]. Journal of Biological Chemistry, 2013, 288(38): 27584-27593.
[24] Chen Y, Dorn G W. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria[J]. Science, 2013, 340(6131): 471-475.
[25] Sheffer R, Douiev L, Edvardson S, et al. Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired mitochondrial fission and function[J]. American Journal of Medical Genetics Part A, 2016, 170(6): 1603-1607.
[26] Amati-Bonneau P, Valentino M L, Reynier P, et al. OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes[J]. Brain, 2008, 131(2): 338-351.
[27] Koirala S, Guo Q, Kalia R, et al. Interchangeable adaptors regulate mitochondrial dynamin assembly for membrane scission[J]. Proceedings of the National Academy of Sciences, 2013, 110(15): E1342-E1351.
[28] Cunningham C N, Baughman J M, Phu L, et al. USP30 and parkinhomeostatically regulate atypical ubiquitin chains on mitochondria[J]. Nature Cell Biology, 2015, 17(2): 160-169.
[29] Rathinam R, Berrier A, Alahari S K. Role of Rho GTPases and their regulators in cancer progression[J]. Front Biosci, 2011, 16(1): 2561-2571.
[30] Tondera D, Czauderna F, Paulick K, et al. The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells[J]. Journal of Cell Science, 2005, 118(14): 3049-3059.
[31] Bandiera S, Matégot R, Girard M, et al. MitomiRs delineating the intracellular localization of microRNAs at mitochondria[J]. Free Radical Biology and Medicine, 2013, 64: 12-19.
[32] Head B, Griparic L, Amiri M, et al. Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells[J]. The Journal of Cell Biology, 2009, 187(7): 959-966.
[33] Stiburek L, Cesnekova J, Kostkova O, et al. YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation[J]. Molecular Biology of the Cell, 2012, 23(6): 1010-1023.
[34] Losón O C, Song Z, Chen H, et al. Fis1, Mff, MiD49, and MiD51 mediate DRP1 recruitment in mitochondrial fission[J]. Molecular Biology of the Cell, 2013, 24(5): 659-667.
[35] Losón O C, Liu R, Rome M E, et al. The mitochondrial fission receptor MiD51 requires ADP as a cofactor[J]. Structure, 2014, 22(3): 367-377.
[36] Regmi S G, Rolland S G, Conradt B. Age-dependent changes in mitochondrial morphology and volume are not predictors of lifespan[J]. Aging (Albany NY), 2014, 6(2): 118.
[37] Yasuda K, Ishii T, Suda H, et al. Age-related changes of mitochondrial structure and function in Caenorhabditiselegans[J]. Mechanisms of Ageing and Development, 2006, 127(10): 763-770.
[38] Labrousse A M, Zappaterra M D, Rube D A, et al. C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane[J]. Molecular Cell, 1999, 4(5): 815-826.
[39] Yang C C, Chen D, Lee S S, et al. The dynamin-related protein DRP-1 and the insulin signaling pathway cooperate to modulate Caenorhabditis elegans longevity[J]. Aging Cell, 2011, 10(4): 724-728.
[40] Kim H, Scimia M C, Wilkinson D, et al. Fine-tuning of DRP1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia[J]. Molecular Cell, 2011, 44(4): 532-544.
[41] Murphy R, Turnbull D M, Walker M, et al. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation[J]. Diabetic Medicine, 2008, 25(4): 383-399.
[42] Toda C, Kim J D, Impellizzeri D, et al. UCP2 regulates mitochondrial fission and ventromedial nucleus control of glucose responsiveness[J]. Cell, 2016, 164(5): 872-883.
[43] Coppola A, Liu Z W, Andrews Z B, et al. A central thermogenic-like mechanism in feeding regulation: An interplay between arcuate nucleus T3 and UCP2[J]. Cell Metabolism, 2007, 5(1): 21-33.
[44] Andrews Z B, Liu Z W, Walllingford N, et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals[J]. Nature, 2008, 454(7206): 846-851.
[45] Diano S, Horvath T L. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism[J]. Trends in Molecular Medicine, 2012, 18(1): 52-58.
[46] Schapira A H V, Cooper J M, Dexter D, et al. Mitochondrial complex Ⅰ deficiency in Parkinson's disease[J]. Journal of Neurochemistry, 1990, 54(3): 823-827.
[47] Devi L, Prabhu B M, Galati D F, et al. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction[J]. The Journal of Neuroscience, 2006, 26(35): 9057-9068.
[48] Gu M, Gash M T, Mann V M, et al. Mitochondrial defect in Huntington's disease caudate nucleus[J]. Annals of Neurology, 1996, 39(3): 385-389.
[49] Schapira A H V. Mitochondrial diseases[J]. The Lancet, 2012, 379(9828): 1825-1834.
[50] Schapira A H, Agid Y, Barone P, et al. Perspectives on recent advances in the understanding and treatment of Parkinson's disease[J]. European Journal of Neurology, 2009, 16(10): 1090-1099.
[51] Valente E M, Abou-Sleiman P M, Caputo V, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1[J]. Science, 2004, 304(5674): 1158-1160.
[52] Roses A D, Lutz M W, Amrine-Madsen H, et al. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease[J]. The Pharmacogenomics Journal, 2010, 10(5): 375-384.
[53] Lim D, Fedrizzi L, Tartari M, et al. Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease[J]. Journal of Biological Chemistry, 2008, 283(9): 5780-5789.
[54] Orr A L, Li S, Wang C E, et al. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking[J]. The Journal of Neuroscience, 2008, 28(11): 2783-2792.
[55] Kaltenbach L S, Romero E, Becklin R R, et al. Huntingtin interacting proteins are genetic modifiers of neurodegeneration[J]. PLoS Genet, 2007, 3(5): e82.
[56] Greaves L C, Reeve A K, Taylor R W, et al. Mitochondrial DNA and disease[J]. The Journal of Pathology, 2012, 226(2): 274-286.
[57] DiMauro S, Davidzon G. Mitochondrial DNA and disease[J]. Annals of Medicine, 2005, 37(3): 222-232.
[58] Wallace D C, Singh G, Lott M T, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy[J]. Science, 1988, 242(4884): 1427.
[59] Kogelnik A M, Lott M T, Brown M D, et al. MITOMAP: A human mitochondrial genome database[J]. Nucleic Acids Research, 1996, 24(1): 177-179.
[60] McFarland R, Taylor R W, Turnbull D M. A neurological perspective on mitochondrial disease[J]. The Lancet Neurology, 2010, 9(8): 829-840.
[61] van den Ouweland J M W, Lemkes H, Ruitenbeek W, et al. Mutation in mitochondrial tRNALeu (UUR) gene in a large pedigree with maternally transmitted type Ⅱ diabetes mellitus and deafness[J]. Nature Genetics, 1992, 1(5): 368-371.
[62] Goto Y I, Nonaka I, Horai S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies[J]. Nature, 1991, 348(6302):651-653.