20 4 2008 4 Chinese Bulletin of Life Sciences Vol. 20, No. 4 Aug., 2008 1004-0374(2008)04-0599-06 Mitofusin 1 421008; 2 200241 Mitofusin 2 Mitofusin Mitofusin Q44 Q244 A Roles of Mitofusin on the pathogenesis, prevention and cure of insulin resistance QI Zheng-tang 1,2,DING Shu-zhe 2 *,HE Jie 1 (1 Department of Physical Education, Hengyang Normal University, Hengyang 421008, China; 2 College of Physical Education and Health, East China Normal University, Shanghai 200241, China) Abstract: Mitofusin was a key regulator of mitochondrial fusion and closely related to insulin resistance and type 2 diabetes. Roles of Mitofusin on the pathogenesis, prevention and cure of insulin resistance were summarized in the review. Key words: Mitofusin mitochondrial fusion insulin resistance [1] Rizzuto [2] [3] [4] mtdna mtdna [5] [6] (ROS) 2008-03-03 2008-04-11 2007 (44038470) * E-mail: szding@tyxx.ecnu.edu.cn
600 Dynamin( ) Mitofusin(Mfn) [7] 1 Mitofusin GTPase Mfn1 Mfn2 [8] N GTPase Mfn1 Mfn2 7 HR1 HR2 [9] Mfn1 Mfn2 60% (Docking) Mfn1 Mfn1 GTPase OPA1(optic atrophy 1) [10] Mfn2 Mfn1 Mfn1 Mfn2 GTPase [11] Mfn1/2 N GTP C HR2 (coiled-coil ) Mfn1/2 Mfn1/2 coiled-coil [12] GTP [13] OPA1 sirna OPA1 [14] OPA1 GTP Margaret Mfn2 (Mfn2 RasG12V ) Mfn2 GTP Mfn2 GTP Mfn2 GTPase Staurosporine Bax Mfn2 Mfn2 Bax c Mfn2 Mfn2 GTPase Mfn2 [15] Mfn2 Mfn2 Ras [16] Mfn2 Florence [17] SNARE D (mitopld) mitopld Mfn [18] 2 Mitofusin (insulin resistance) ( ) 2 mtdna 2 [19] Lowell Shulman [20] (MRS) 2 Mitofusin 2.1 Mitofusin [21] Fzo1A/B Fzo1A/B Fzo1A/B Mfn1/2 Fzo1A/B c Bax/Bak Mfn Drp1 [22]
Mitofusin 601 2.2 Mitofusin ROS Mfn2 [15] ROS Mfn2 ROS ROS Mfn2 ROS ROS Mitofusin ROS Time-lapse [23] 2 ROS Mitofusin ROS 2.3 Mitofusin [1] Mfn2 [24] Mfn2 [25] Mfn2 Mfn2 TNFα/IL-6 Mfn2 [26] Mfn2 [27] Mfn2 3 PCG-1α Mfn2 PGC-1α (PPARs) PPARγ PGC-1α PGC-1α 2 [28] PGC-1α Mfn1/2 OPA1 Drp1 Fis1 PGC-1α Mfn2 Mfn2 PGC-1α Mfn2 PGC-1α Mfn2 PGC-1α PGC-1α Mfn2-413/-398 ERRα( ) Mfn2 PGC- 1α Mfn2 PGC-1α mrna PGC-1α ERRα Mfn2 2 [29] Pawlikowska [30] Mfn2 PI3K Mfn2 [30] PGC-1α-Mfn2 PGC-1α Mfn2 2 PGC-1α Mfn2 [31] Mfn2 [32] PGC-1α GLUT4 [33] PGC-1α Mfn2 PGC-1α Mfn2 [26] PGC-1α Mfn2 [34] PGC-1α mrna Mfn2 [35] Zucker 2 Mfn2 mrna [1] PGC-1α G482S 2 [36] 2 PGC-1α PGC-1α 2 PGC-1α [37]
602 PGC-1α 2 [38] Mitofusin PCG-1α 2 PGC-1α- Mfn2 4 Mitofusin 2 II I Mitofusin Mitofusin Mfn2 ( β3- ) [29] Mfn2 2 24h Mfn1 Mfn2 mrna PGC-1α ERRα Mfn1 Mfn2 COXIV mrna 24h PGC-1α ERRα mrna 2h PGC-1α/ERRα Mfn1/Mfn2 Mfn2 PGC-1α/ERRα PGC-1α [39] Mfn2 PGC- 1α mrna Mfn2 PCG-1α ERRα [40] PGC-1α 1 PGC-1α/NRF-1, 2 PGC-1α/Mfn2
Mitofusin 603 Mfn2 ( 1) [1] Mcbride H, Neuspiel M, Wasiak S. Mitochondria: More than just a powerhouse. Curr Biol, 2006, 16(14): R551-60 [2] Rizzuto R, Pinton P, Carrington W, et al. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca 2+ responses. Science, 1998, 280(5370): 1763-6 [3] Karbowski M, Youle R. Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ, 2003, 10(8): 870-80 [4] Chen H, Chan DC. Mitochondrial dynamics in mammals. Curr Top Dev Biol, 2004, 59: 119-44 [5] Collins T, Berridge M, Lipp P. Mitochondria are morphologically and functionally heterogeneous within cells. EMBO J, 2002, 21(7): 1616-27 [6] Margineantu DH, Gregory Cox W, Sundell L, et al. Cell cycle dependent morphology changes and associated mitochondrial DNA redistribution in mitochondria of human cell lines. Mitochondrion, 2002, 1(5): 425-35 [7],.., 2006, 28(5): 671-5 [8] Chen HC, Detmer SA, Ewald AJ, et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol, 2003, 160(2):189-200 [9] Koshiba T, Detmer SA, Kaiser JT, et al. Structural basis of mitochondrial tethering by mitofusin complexes. Science, 2004, 305(5685): 858-62 [10] Cipolat S, de Brito OM, Dal Zilio B, et al. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA, 2004, 101(45): 15927-32 [11] Eura Y, Ishihara N, Yokota S, et al. Two mitofusin proteins, mammalian homologues of FZO, with distinct functions are both required for mitochondrial fusion. J Biochem, 2003, 134(3): 333-44 [12] Karbowski M, Norris KL, Cleland MM, et al. Role of bax and bak in mitochondrial morphogenesis. Nature, 2006, 443 (7112): 658-62 [13] Ishihara N, Eura Y, Mihara K. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J Cell Sci, 2004, 117(26): 6535-46 [14] Olichon A, Baricault L, Gas N, et al. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem, 2003, 278(10): 7743-6 [15] Neuspiel M, Zunino R, Gangaraju S, et al. Activated mitofusin 2 signals mitochondrial fusion, interferes with bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem, 2005, 280(26): 25060-70 [16] Chen KH, Guo XM, Ma DL, et al. Dysregulation of a novel hyperplasia suppressor gene triggers vascular proliferative disorders. Nat Cell Biol, 2004, 6(9): 872-83 [17] Florence M, Olwenn G, Carmen C. Separate fusion of outer and inner mitochondrial membranes. Nature, 2005, 6(9): 853-9 [18] Choi SY, Huang P, Jenkins GM, et al. A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nat Cell Biol, 2006, 8(11): 1255-62 [19] Petersen K, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science, 2003, 300(5622): 1140-2 [20] Lowell B, Shulman G. Mitochondrial dysfunction and type 2 diabetes. Science, 2005, 307(5708): 384-7 [21] Richard JY, Mariusz K. Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol, 2005, 6(8): 657-63 [22] Sugioka R, Shimizu S, Tsujimoto Y. Fzo1, aprotein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem, 2004, 279(50): 52726-34 [23] Yu TZ, James L, Robotham JL, et al. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA, 2006, 103(8): 2653-8 [24] Bach D, Pich S, Soriano F, et al. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem, 2003, 278(19): 17190-7 [25] Debard C, Laville M, Berbe V, et al. Expression of key genes of fatty acid oxidation, including adiponectin receptors, in skeletal muscle of type 2 diabetic patients. Diabetologia, 2004, 47(5): 917-25 [26] Bach D, Naon D, Pich S. Expression of Mfn2, the charcotmarie-tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor α and interleukin- 6. Diabetes, 2005, 54(9): 2685-93 [27] Mingrone G, Manco M, Calvani M. Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity? Diabetologia, 2005, 48(10): 2108-14 [28] Franks P, Loos R. PGC-1α gene and physical activity in type 2 diabetes mellitus. Exerc Sport Sci Rev, 2006, 34(4): 171-5 [29] Soriano F, Liesa M, Bach D, et al. Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator activated receptor-γ coactivator-1α, estrogen-related receptor-α, and mitofusin 2. Diabetes, 2006, 55(6): 1783-91 [30] Pawlikowska P, Gajkowska B, Orzechowski A. Mitofusin 2 (Mfn2): a key player in insulin-dependent myogenesis in vitro. Cell Tissue Res, 2007, 327(3): 571-81 [31] Liang H, Ward W. PGC-1α: a key regulator of energy metabolism. Adv Physiol Educ, 2006, 30(4): 145-51 [32] Pich S, Bach D, Briones P, et al.the charcot-marie-tooth type 2A gene product, Mfn2, upregulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet, 2005, 14 (11): 1405-15 [33] Michael L, Wu ZD, Cheatham R, et al. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci USA, 2001, 98(7): 3820-5 [34] Holloszy J. Exercise-induced increase in muscle insulin sensitivity. J Appl Physiol, 2005, 99(1): 338-43
604 [35] Gastaldi G, Russell A,Golay A, et al. Upregulation of peroxisome proliferator-activated receptor γ coactivator gene during weight loss is related to insulin sensitivity but not to energy expenditure. Diabetologia, 2007, 50(11): 2348-55 [36] Soyal S, Krempler F, Oberkofler H, et al. PGC-1α: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes. Diabetologia, 2006, 49(7): 1477-88 [37] Mootha V, Lindgren C, Eriksson K, et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet, 2003, 34(3): 267-73 [38] Ling C, Poulsen P, Carlsson E, et al. Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins. J Clin Invest, 2004, 114 (10): 1518-26 [39] Cartoni R, L ger B, Hock MB, et al. Mitofusins 1/2 and ERR α expression are increased in human skeletal muscle after physical exercise. J Physiol, 2005, 567(Pt 1): 349-58 [40] Garnier A, Fortin D, Zoll J, et al. Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle. FASEB J, 2005, 19(1): 43-52