Research Progress of Relationship between Mitochondrial Fusion Protein 1，Mitochondrial Fusion Protein 2 and Physiological Function of Cardiomyocyte_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LI Xianshuai , MU Junsheng.

Department of Cardiac Surgery，BeijingAnzhen Hospital，Capital Medical University，Beijing 100029，P. R. China;

Corresponding author：

Keywords：

Mitochondrial fusion protein; 　Mitochondria; 　Cardiomyocyte; 　Physiological function

DOI：

10.7507/1007-4848.20130137

Video：

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The main function of mitochondrial fusion protein 1 （Mfn1） and mitochondrial fusion protein 2 （Mfn2） was originally thought to be just regulating the fusion of mitochondrial outer membrane. But in recent years，many studies on these two proteins show that they are involved in many important cellular physiological processes including proliferation，apoptosis，necrosis and regulation of respiratory function and oxidative metabolism. There are many aspects of the influenceof Mfn1 and Mfn2 on cardiomyocyte，which have not been thoroughly studied yet，sometimes with even contradictoryconclusions. But these two proteins definitely have significant impact on the growth，development and physiological functionof cardiomyocyte. To investigate the function and mechanism of Mfn1 and Mfn2 in various physiological processes of cardiomyocyte is of great significance for in vitro studies of physiological functions of cardiomyocyte and technological development of myocardial tissue engineering and transplantation in vivo. This article mainly focuses on recent research progress of the influence of Mfn1 and Mfn2 on various physiological functions of cardiomyocyte.

Citation： LI Xianshuai,MU Junsheng.. Research Progress of Relationship between Mitochondrial Fusion Protein 1，Mitochondrial Fusion Protein 2 and Physiological Function of Cardiomyocyte. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2013, 20(4): 457-462. doi: 10.7507/1007-4848.20130137 Copy

1.	Cho YM， Kwon S， Pak YK， et al. Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneousdifferentiation of human embryonic stem cells. Biochem Biophys Res Commun， 2006， 348 （4）：1472-1478.
2.	Ono T， Isobe K， Nakada K， et al. Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet， 2001， 28 （3）：272-275.
3.	Zhang DD， Ma C， Li SS， et al. Effect of mitofusin 2 on smooth muscle cells proliferation in hypoxic pulmonary hypertension.Microvasc Res， 2012， 84 （3）：286-296.
4.	Shen T， Zheng M， Cao CM， et al. Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis. J Biol Chem， 2007， 282 （32）：23354-23361.
5.	Whelan RS， Konstantinidis K， Wei AC， et al. Bax regulates primarynecrosis through mitochondrial dynamics. Proc Natl Acad Sci U S A.2012， 109 （17）：6566-6571.
6.	Lugus JJ， Ngoh GA， Bachschmid MM， et al. Mitofusins arerequired for angiogenic function and modulate different signaling pathways in cultured endothelial cells. J Mol Cell Cardiol， 2011， 51 （6）：885-893.
7.	Gentil BJ， Minotti S， Beange M， et al. Normal role of the low-molecular-weight neurofilament protein in mitochondrial dynamics and disruption in Charcot-Marie-Tooth disease. FASEB J， 2012， 26 （3）：1194-1203.
8.	Mccoy MK， Cookson MR. Mitochondrial quality control anddynamics in Parkinson’s disease. Antioxid Redox Signal， 2012， 16 （9）：869-882.
9.	Reddy PH， Tripathi R， Troung Q， et al. Abnormal mitochondrialdynamics and synaptic degeneration as early events in Alzheimer’sdisease：implications to mitochondria-targeted antioxidant therapeutics.Biochim Biophys Acta， 2012， 1822 （5）：639-649.
10.	Santel A， Frank S， Gaume B， et al. Mitofusin-1 protein is a generallyexpressed mediator of mitochondrial fusion in mammalian cells. J Cell Sci， 2003， 116 （13）：2763-2774.
11.	Koshiba T， Detmer SA， Kaiser JT， et al. Structural basis of mitochondrial tethering by mitofusin complexes. Science， 2004， 305 （5685）：858-862.
12.	Chen H， Detmer SA， Ewald AJ， et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embr-yonic development. J Cell Biol， 2003， 160 （2）：189-200.
13.	Mackler B， Grace R， Tippit DF， et al. Studies of the development of congenital anomalies in rats.Ⅲ. Effects of inhibition of mitochondrial energy systems on embryonic development. Teratology， 1975， 12 （3）：291-296.
14.	George A， Porter J， Jennifer H， et al. Bioenergetics， mitochondria， and cardiac myocyte differentiation. Prog Pediatr Cardiol， 2011， 31 （2）：75-81.
15.	Prowse AB， Chong F， Elliott DA， et al. Analysis of mitochondrial function and localisation during human embryonic stem cell differentiation in vitro. PLoS One， 2012， 7 （12）：e52214.
16.	Ong SB， Subrayan S， Lim SY， et al. Inhibiting mitochondrial fissionprotects the heart against ischemia/reperfusion injury. Circulation， 2010， 121 （18）：2012-2022.
17.	Chen Y， Liu YQ， Dorn GW 2nd. Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res， 2011， 109 （12）：1327-1331.
18.	Papanicolaou KN， Kikuchi R， Ngoh GA， et al. Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ Res， 2012， 111 （8）：1012-1026.
19.	Dorn GW 2nd， Clark CF， Eschenbacher WH， et al. MARF and Opa1 control mitochondrial and cardiac function in Drosophila. Circ Res， 2011， 108 （1）：12-17.
20.	Eschenbacher WH， Song MS， Chen Y， et al. Two rare human mitofusin 2 mutations alter mitochondrial dynamics and induce retinal and cardiac pathology in Drosophila. PLoS One， 2012， 7 （9）：e44296.
21.	Parra V， Eisner V， Chiong M， et al. Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res， 2008， 77 （2）：387-397.
22.	Fang L， Moore XL， Gao XM， et al. Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo. Life Sci， 2007， 80 （23）：2154-2160.
23.	陈春蕾，沈涛. 郑铭，等. 线粒体融合蛋白Mfn2对心肌细胞肥大的抑制作用. 北京大学学报， 2008， 40 （5）：528-532.
24.	Yu HY， Guo YH， Mi L， et al. Mitofusin 2 inhibits angiotensinⅡ -induced myocardial hypertrophy. J Cardiovasc Pharmacol Ther， 2011， 16 （2）：205-211.
25.	Papanicolaou KN， Khairallah RJ， Ngoh GA， et al. Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol， 2011， 31 （6）：1309-1328.
26.	Papanicolaou KN， Ngoh GA， Dabkowski ER， et al. Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol， 2012， 302 （1）：H167-H179.
27.	de Brito OM， Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature， 2008， 456 （7222）：605-610.
28.	de Brito OM， Scorrano L. Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering：the role of Ras. Mitochondrion， 2009， 9 （3）：222-226.
29.	Ngoh GA， Papanicolaou KN， Walsh K. Loss of mitofusin 2 promotesendoplasmic reticulum stress. J Biol Chem， 2012， 287 （24）：20321-20332.
30.	Zhao T， Huang XH， Han L， et al. Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes. J Biol Chem， 2012， 287 （28）：23615-23625.

1. 　Cho YM， Kwon S， Pak YK， et al. Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneousdifferentiation of human embryonic stem cells. Biochem Biophys Res Commun， 2006， 348 （4）：1472-1478.
2. 　Ono T， Isobe K， Nakada K， et al. Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet， 2001， 28 （3）：272-275.
3. 　Zhang DD， Ma C， Li SS， et al. Effect of mitofusin 2 on smooth muscle cells proliferation in hypoxic pulmonary hypertension.Microvasc Res， 2012， 84 （3）：286-296.
4. 　Shen T， Zheng M， Cao CM， et al. Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis. J Biol Chem， 2007， 282 （32）：23354-23361.
5. 　Whelan RS， Konstantinidis K， Wei AC， et al. Bax regulates primarynecrosis through mitochondrial dynamics. Proc Natl Acad Sci U S A.2012， 109 （17）：6566-6571.
6. 　Lugus JJ， Ngoh GA， Bachschmid MM， et al. Mitofusins arerequired for angiogenic function and modulate different signaling pathways in cultured endothelial cells. J Mol Cell Cardiol， 2011， 51 （6）：885-893.
7. 　Gentil BJ， Minotti S， Beange M， et al. Normal role of the low-molecular-weight neurofilament protein in mitochondrial dynamics and disruption in Charcot-Marie-Tooth disease. FASEB J， 2012， 26 （3）：1194-1203.
8. 　Mccoy MK， Cookson MR. Mitochondrial quality control anddynamics in Parkinson’s disease. Antioxid Redox Signal， 2012， 16 （9）：869-882.
9. 　Reddy PH， Tripathi R， Troung Q， et al. Abnormal mitochondrialdynamics and synaptic degeneration as early events in Alzheimer’sdisease：implications to mitochondria-targeted antioxidant therapeutics.Biochim Biophys Acta， 2012， 1822 （5）：639-649.
10. 　Santel A， Frank S， Gaume B， et al. Mitofusin-1 protein is a generallyexpressed mediator of mitochondrial fusion in mammalian cells. J Cell Sci， 2003， 116 （13）：2763-2774.
11. 　Koshiba T， Detmer SA， Kaiser JT， et al. Structural basis of mitochondrial tethering by mitofusin complexes. Science， 2004， 305 （5685）：858-862.
12. 　Chen H， Detmer SA， Ewald AJ， et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embr-yonic development. J Cell Biol， 2003， 160 （2）：189-200.
13. 　Mackler B， Grace R， Tippit DF， et al. Studies of the development of congenital anomalies in rats.Ⅲ. Effects of inhibition of mitochondrial energy systems on embryonic development. Teratology， 1975， 12 （3）：291-296.
14. 　George A， Porter J， Jennifer H， et al. Bioenergetics， mitochondria， and cardiac myocyte differentiation. Prog Pediatr Cardiol， 2011， 31 （2）：75-81.
15. 　Prowse AB， Chong F， Elliott DA， et al. Analysis of mitochondrial function and localisation during human embryonic stem cell differentiation in vitro. PLoS One， 2012， 7 （12）：e52214.
16. 　Ong SB， Subrayan S， Lim SY， et al. Inhibiting mitochondrial fissionprotects the heart against ischemia/reperfusion injury. Circulation， 2010， 121 （18）：2012-2022.
17. 　Chen Y， Liu YQ， Dorn GW 2nd. Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res， 2011， 109 （12）：1327-1331.
18. 　Papanicolaou KN， Kikuchi R， Ngoh GA， et al. Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ Res， 2012， 111 （8）：1012-1026.
19. 　Dorn GW 2nd， Clark CF， Eschenbacher WH， et al. MARF and Opa1 control mitochondrial and cardiac function in Drosophila. Circ Res， 2011， 108 （1）：12-17.
20. 　Eschenbacher WH， Song MS， Chen Y， et al. Two rare human mitofusin 2 mutations alter mitochondrial dynamics and induce retinal and cardiac pathology in Drosophila. PLoS One， 2012， 7 （9）：e44296.
21. 　Parra V， Eisner V， Chiong M， et al. Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res， 2008， 77 （2）：387-397.
22. 　Fang L， Moore XL， Gao XM， et al. Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo. Life Sci， 2007， 80 （23）：2154-2160.
23. 　陈春蕾，沈涛. 郑铭，等. 线粒体融合蛋白Mfn2对心肌细胞肥大的抑制作用. 北京大学学报， 2008， 40 （5）：528-532.
24. 　Yu HY， Guo YH， Mi L， et al. Mitofusin 2 inhibits angiotensinⅡ -induced myocardial hypertrophy. J Cardiovasc Pharmacol Ther， 2011， 16 （2）：205-211.
25. 　Papanicolaou KN， Khairallah RJ， Ngoh GA， et al. Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol， 2011， 31 （6）：1309-1328.
26. 　Papanicolaou KN， Ngoh GA， Dabkowski ER， et al. Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol， 2012， 302 （1）：H167-H179.
27. 　de Brito OM， Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature， 2008， 456 （7222）：605-610.
28. 　de Brito OM， Scorrano L. Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering：the role of Ras. Mitochondrion， 2009， 9 （3）：222-226.
29. 　Ngoh GA， Papanicolaou KN， Walsh K. Loss of mitofusin 2 promotesendoplasmic reticulum stress. J Biol Chem， 2012， 287 （24）：20321-20332.
30. 　Zhao T， Huang XH， Han L， et al. Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes. J Biol Chem， 2012， 287 （28）：23615-23625.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Research Progress of Relationship between Mitochondrial Fusion Protein 1，Mitochondrial Fusion Protein 2 and Physiological Function of Cardiomyocyte

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