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http://dx.doi.org/10.4062/biomolther.2010.18.3.235

Mitochondria: The Secret Chamber of Therapeutic Targets for Age-Associated Degenerative Diseases  

KimPak, Young-Mi (Department of Physiology, College of Medicine, Kyung Hee University)
Jeong, Jae-Hoon (Department of Life and Nanopharmaceutical Science, College of Medicine, Kyung Hee University)
Publication Information
Biomolecules & Therapeutics / v.18, no.3, 2010 , pp. 235-245 More about this Journal
Abstract
Mitochondria have long been recognized as ATP engines for the cell and recently as a dynamic and mobile organelles that control cell death and life. This exquisite organelle is the site of reactive oxygen species production and is highly vulnerable to exogenous stresses, resulting in catastrophic damage to the cell. Mitochondrial dysfunction is linked to a wide range of age-associated degenerative diseases, such as metabolic syndrome, cardiovascular disease, and neurodegenerative diseases. Understanding the molecular mechanisms of mitochondria-dependent pathogenesis may provide important strategies to treat these diseases. Indeed, mitochondria are emerging therapeutic targets for the mitochondria-related diseases. In this paper, we review the recent concepts of mitochondrial biology and how mitochondria are involved in age-associated degenerative diseases. Furthermore, we summarize the therapeutics which target to improve mitochondrial functions.
Keywords
Mitochondria; Degenerative disease; Therapeutic; Mitochondrial medicine;
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1 Wagner, B. K., Kitami, T., Gilbert, T. J., Peck, D., Ramanathan,A., Schreiber, S. L., Golub, T. R. and Mootha, V. K. (2008).Large-scale chemical dissection of mitochondrial function.Nat. Biotechnol. 26, 343-351.   DOI   ScienceOn
2 Wallace, D. C. (2005). A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359-407.   DOI   ScienceOn
3 Wang, X. and Schwarz, T. L. (2009). The mechanism of $Ca^{2+}$ - dependent regulation of kinesin-mediated mitochondrial motility. Cell 136, 163-174.   DOI   ScienceOn
4 Wang, Y., Michikawa, Y., Mallidis, C., Bai, Y., Woodhouse, L.,Yarasheski, K. E., Miller, C. A., Askanas, V., Engel, W. K.,Bhasin, S. and Attardi, G. (2001). Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication. Proc. Natl. Acad. Sci. U S A 98, 4022-4027.   DOI   ScienceOn
5 Yankner, B. A., Lu, T. and Loerch, P. (2008). The aging brain.Annu. Rev. Pathol. 3, 41-66.   DOI   ScienceOn
6 Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M. andSpiegelman, B. M. (1998). A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92,829-839.   DOI   ScienceOn
7 Saha, S., Guillily, M. D., Ferree, A., Lanceta, J., Chan, D.,Ghosh, J., Hsu, C. H., Segal, L., Raghavan, K., Matsumoto,K., Hisamoto, N., Kuwahara, T., Iwatsubo, T., Moore, L.,Goldstein, L., Cookson, M. and Wolozin, B. (2009). LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J. Neurosci. 29, 9210-9218.   DOI   ScienceOn
8 Schapira, A. H. (2006). Mitochondrial disease. Lancet. 368, 70-82.   DOI   ScienceOn
9 Silva, J. P., Kohler, M., Graff, C., Oldfors, A., Magnuson, M. A.,Berggren, P. O. and Larsson, N. G. (2000). Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nat. Genet. 26, 336-340.   DOI   ScienceOn
10 Song, J., Oh, J. Y., Sung, Y. A., Pak, Y. K., Park, K. S. and Lee,H. K. (2001). Peripheral blood mitochondrial DNA content is related to insulin sensitivity in offspring of type 2 diabetic patients. Diabetes Care 24, 865-869.   DOI   ScienceOn
11 Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., Bae, E.,Kim, J., Shong, M., Kim, J. M. and Chung, J. (2006). Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157-1161.   DOI   ScienceOn
12 Trifunovic, A., Hansson, A., Wredenberg, A., Rovio, A. T., Dufour,E., Khvorostov, I., Spelbrink, J. N., Wibom, R., Jacobs, H. T.and Larsson, N. G. (2005). Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl. Acad. Sci. U S A 102, 17993-17998.   DOI   ScienceOn
13 Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N.,Rovio, A. T., Bruder, C. E., Bohlooly, Y. M., Gidlof, S., Oldfors,A., Wibom, R., Tornell, J., Jacobs, H. T. and Larsson, N. G.(2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417-423.   DOI   ScienceOn
14 Twig, G., Elorza, A., Molina, A. J., Mohamed, H., Wikstrom, J.D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G.,Alroy, J., Wu, M., Py, B. F., Yuan, J., Deeney, J. T., Corkey,B. E. and Shirihai, O. S. (2008). Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433-446.   DOI   ScienceOn
15 Park, K. S., Nam, K. J., Kim, J. W., Lee, Y. B., Han, C. Y., Jeong,J. K., Lee, H. K. and Pak, Y. K. (2001). Depletion of mitochondrial DNA alters glucose metabolism in SK-Hep1 cells. Am. J. Physiol. Endocrinol. Metab. 280, E1007-1014.   DOI
16 Park, K. S., Song, J. H., Lee, K. U., Choi, C. S., Koh, J. J., Shin,C. S. and Lee, H. K. (1999). Peripheral blood mitochondrial DNA content correlates with lipid oxidation rate during euglycemic clamps in healthy young men. Diabetes Res. Clin. Pract. 46, 149-154.   DOI   ScienceOn
17 Park, K. S., Wiederkehr, A., Kirkpatrick, C., Mattenberger, Y.,Martinou, J. C., Marchetti, P., Demaurex, N. and Wollheim,C. B. (2008). Selective actions of mitochondrial fission/fusion genes on metabolism-secretion coupling in insulin-releasing cells. J. Biol. Chem. 283, 33347-33356.   DOI
18 Petersen, K. F., Befroy, D., Dufour, S., Dziura, J., Ariyan, C.,Rothman, D. L., DiPietro, L., Cline, G. W. and Shulman, G. I.(2003). Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140-1142.   DOI
19 Patti, M. E., Butte, A. J., Crunkhorn, S., Cusi, K., Berria, R.,Kashyap, S., Miyazaki, Y., Kohane, I., Costello, M., Saccone,R., Landaker, E. J., Goldfine, A. B., Mun, E., DeFronzo, R.,Finlayson, J., Kahn, C. R. and Mandarino, L. J. (2003).Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc. Natl. Acad. Sci. U S A 100,8466-8471.   DOI   ScienceOn
20 Perry, G. M., Tallaksen-Greene, S., Kumar, A., Heng, M. Y.,Kneynsberg, A., van Groen, T., Detloff, P. J., Albin, R. L. andLesort, M. (2010). Mitochondrial calcium uptake capacity as a therapeutic target in the R6/2 mouse model of Huntington's disease. Hum. Mol. Genet. in press.
21 Petersen, K. F., Dufour, S., Befroy, D., Garcia, R. and Shulman,G. I. (2004). Impaired mitochondrial activity in the insulinresistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350, 664-671.   DOI   ScienceOn
22 Lustbader, J. W., Cirilli, M., Lin, C., Xu, H. W., Takuma, K.,Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M.,Trinchese, F., Liu, S., Gunn-Moore, F., Lue, L. F., Walker, D.G., Kuppusamy, P., Zewier, Z. L., Arancio, O., Stern, D.,Yan, S. S. and Wu, H. (2004). ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 304, 448-452.   DOI
23 MacAskill, A. F. and Kittler, J. T. (2010). Control of mitochondrial transport and localization in neurons. Trends Cell Biol. 20, 102-112.   DOI
24 Madamanchi, N. R. and Runge, M. S. (2007). Mitochondrial dysfunction in atherosclerosis. Circ. Res. 100, 460-473.   DOI
25 Matsushima, Y., Garesse, R. and Kaguni, L. S. (2004). Drosophila mitochondrial transcription factor B2 regulates mitochondrial DNA copy number and transcription in schneider cells. J. Biol. Chem. 279, 26900-26905.   DOI
26 Narendra, D., Tanaka, A., Suen, D. F. and Youle, R. J. (2008).Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795-803.   DOI   ScienceOn
27 McBride, H. M. (2008). Parkin mitochondria in the autophagosome.J. Cell. Biol. 183, 757-759.   DOI   ScienceOn
28 Michikawa, Y., Mazzucchelli, F., Bresolin, N., Scarlato, G. andAttardi, G. (1999). Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286, 774-779.   DOI
29 Milne, J. C., Lambert, P. D., Schenk, S., Carney, D. P., Smith, J.J., Gagne, D. J., Jin, L., Boss, O., Perni, R. B., Vu, C. B.,Bemis, J. E., Xie, R., Disch, J. S., Ng, P. Y., Nunes, J. J.,Lynch, A. V., Yang, H., Galonek, H., Israelian, K., Choy, W.,Iffland, A., Lavu, S., Medvedik, O., Sinclair, D. A., Olefsky, J.M., Jirousek, M. R., Elliott, P. J. and Westphal, C. H. (2007).Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712-716.   DOI   ScienceOn
30 Okamoto, K. and Shaw, J. M. (2005). Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu. Rev. Genet. 39, 503-536.   DOI   ScienceOn
31 Lee, C. K., Allison, D. B., Brand, J., Weindruch, R. and Prolla, T.A. (2002). Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc. Natl. Acad. Sci. U S A 99, 14988-14993.   DOI
32 Lee, H. K., Park, K. S., Cho, Y. M., Lee, Y. Y. and Pak, Y. K.(2005). Mitochondria-based model for fetal origin of adult disease and insulin resistance. Ann. N Y Acad. Sci. 1042,1-18.   DOI
33 Lee, H. K., Song, J. H., Shin, C. S., Park, D. J., Park, K. S., Lee,K. U. and Koh, C. S. (1998). Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Res. Clin. Pract. 42, 161-167.   DOI
34 Lim, S., Ahn, S. Y., Song, I. C., Chung, M. H., Jang, H. C., Park,K. S., Lee, K. U., Pak, Y. K. and Lee, H. K. (2009). Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance. PLoS One 4, e5186.   DOI   ScienceOn
35 Lee, J., Boo, J. H. and Ryu, H. (2009). The failure of mitochondria leads to neurodegeneration: Do mitochondria need a jump start? Adv. Drug Deliv. Rev. 61, 1316-1323.   DOI
36 Leone, T. C., Lehman, J. J., Finck, B. N., Schaeffer, P. J.,Wende, A. R., Boudina, S., Courtois, M., Wozniak, D. F.,Sambandam, N., Bernal-Mizrachi, C., Chen, Z., Holloszy, J.O., Medeiros, D. M., Schmidt, R. E., Saffitz, J. E., Abel, E. D.,Semenkovich, C. F. and Kelly, D. P. (2005). PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol. 3, e101.   DOI
37 Liang, H. and Ward, W. F. (2006). PGC-1alpha: a key regulator of energy metabolism. Adv. Physiol. Educ. 30, 145-151.   DOI
38 Lin, M. T. and Beal, M. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443,787-795.   DOI
39 Hoppins, S., Lackner, L. and Nunnari, J. (2007). The machines that divide and fuse mitochondria. Annu. Rev. Biochem. 76, 751-780.   DOI
40 Kim, J. A., Wei, Y. and Sowers, J. R. (2008). Role of mitochondrial dysfunction in insulin resistance. Circ. Res. 102, 401-414.   DOI
41 Kujoth, G. C., Hiona, A., Pugh, T. D., Someya, S., Panzer, K.,Wohlgemuth, S. E., Hofer, T., Seo, A. Y., Sullivan, R., Jobling,W. A., Morrow, J. D., Van Remmen, H., Sedivy, J. M., Yamasoba,T., Tanokura, M., Weindruch, R., Leeuwenburgh, C.and Prolla, T. A. (2005). Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481-484.   DOI
42 Larsson, N. G. (2010). Somatic mitochondrial DNA mutations in mammalian aging. Annu. Rev. Biochem. 79, 683-706.   DOI
43 Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H.,Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P.,Elliott, P., Geny, B., Laakso, M., Puigserver, P. and Auwerx,J. (2006). Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127, 1109-1122.   DOI
44 Lane, N. (2006a). Cell biology: power games. Nature 443, 901-903.   DOI
45 Lane, N. (2006b). Mitochondrial disease: powerhouse of disease.Nature 440, 600-602.   DOI   ScienceOn
46 Larsson, N. G. and Rustin, P. (2001). Animal models for respiratory chain disease. Trends Mol. Med. 7, 578-581.   DOI
47 Larsson, N. G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin,P., Lewandoski, M., Barsh, G. S. and Clayton, D. A. (1998).Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat. Genet. 18,231-236.   DOI
48 Cho, D. H., Nakamura, T., Fang, J., Cieplak, P., Godzik, A., Gu,Z. and Lipton, S. A. (2009). S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324, 102-105.   DOI   ScienceOn
49 Choi, Y. S., Hong, J. M., Lim, S., Ko, K. S. and Pak, Y. K. (2006).Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (TFAM) promoter. Biochem. Biophys. Res. Commun. 344,708-712.   DOI
50 Choi, Y. S., Lee, K. U. and Pak, Y. K. (2004). Regulation of mitochondrial transcription factor A expression by high glucose.Ann. N Y Acad. Sci. 1011, 69-77.   DOI
51 Frantz, M. C. and Wipf, P. (2010). Mitochondria as a target in treatment. Environ. Mol. Mutagen. 51, 462-475.
52 Cortopassi, G. A., Shibata, D., Soong, N. W. and Arnheim, N.(1992). A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc. Natl. Acad. Sci. U S A 89, 7370-7374.   DOI
53 Ekstrand, M. I., Falkenberg, M., Rantanen, A., Park, C. B.,Gaspari, M., Hultenby, K., Rustin, P., Gustafsson, C. M. andLarsson, N. G. (2004). Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum. Mol. Genet. 13, 935-944.   DOI
54 Falkenberg, M., Larsson, N. G. and Gustafsson, C. M. (2007).DNA replication and transcription in mammalian mitochondria.Annu. Rev. Biochem. 76, 679-699.   DOI
55 Fujitani, Y., Ueno, T. and Watada, H. (2010). Autophagy in health and disease. 4. The role of pancreatic beta-cell autophagy in health and diabetes. Am. J. Physiol. Cell Physiol.299, C1-6.   DOI
56 Gaspari, M., Falkenberg, M., Larsson, N. G. and Gustafsson, C. M. (2004). The mitochondrial RNA polymerase contributes critically to promoter specificity in mammalian cells. EMBO. J. 23, 4606-4614.   DOI
57 Capaldi, R. A. (2000). The changing face of mitochondrial research.Trends Biochem. Sci. 25, 212-214.   DOI
58 Wallace, D. C., Fan, W. and Procaccio, V. (2010). Mitochondrial energetics and therapeutics. Annu. Rev. Pathol. 5, 297-348.   DOI   ScienceOn
59 Ahn, S. Y., Choi, Y. S., Koo, H. J., Jeong, J. H., Park, W. H.,Kim, M., Piao, Y. and Pak, Y. K. (2010). Mitochondrial dysfunction enhances the migration of vascular smooth muscle cells via suppression of Akt phosphorylation. Biochim. Biophys. Acta. 1800, 275-281.   DOI   ScienceOn
60 Barja, G. and Herrero, A. (2000). Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB. J. 14, 312-318.   DOI
61 Chan, D. C. (2006a). Mitochondria: dynamic organelles in disease, aging, and development. Cell 125, 1241-1252.   DOI
62 Chan, D. C. (2006b). Mitochondrial fusion and fission in mammals.Annu. Rev. Cell Dev. Biol. 22, 79-99.   DOI
63 Chen, H. and Chan, D. C. (2009). Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum. Mol. Genet. 18, R169-176.   DOI