Browse > Article
http://dx.doi.org/10.14348/molcells.2016.0125

Uncoupling Protein, UCP-4 May Be Involved in Neuronal Defects During Aging and Resistance to Pathogens in Caenorhabditis elegans  

Cho, Injeong (Department of Biology Education, College of Education, Chosun University)
Hwang, Gyu Jin (Department of Biology Education, College of Education, Chosun University)
Cho, Jeong Hoon (Department of Biology Education, College of Education, Chosun University)
Abstract
Uncoupling proteins (UCPs) are mitochondrial inner membrane proteins that function to dissipate proton motive force and mitochondrial membrane potential. One UCP has been identified in Caenorhabditis elegans (C. elegans), namely UCP-4. In this study, we examined its expression and localization using a GFP marker in C. elegans. ucp-4 was expressed throughout the body from early embryo to aged adult and UCP-4 was localized in the mitochondria. It is known that increased mitochondrial membrane protential leads to a reactive oxygen species (ROS) increase, which is associated with age-related diseases, including neurodegenerative diseases in humans. A ucp-4 mutant showed increased mitochondrial membrane protential in association with increased neuronal defects during aging, and the neurons of ucp-4 overexpressing animals showed decreased neuronal defects during aging. These results suggest that UCP-4 may be involved in neuroprotection during aging via relieving mitochondrial membrane protential. We also investigated the relationship between UCP-4 and innate immunity because increased ROS can affect innate immunity. ucp-4 mutant displayed increased resistance to the pathogen Staphylococcus aureus compared to wild type. The enhanced immunity in the ucp-4 mutant could be related to increased mitochondrial membrane protential, presumably followed by increased ROS. In summary, UCP-4 might have an important role in neuronal aging and innate immune responses through mediating mitochondrial membrane protential.
Keywords
C. elegans; innate immune; mitochondrial membrane potential(${\Psi}_m$); neuronal defects; ucp-4;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Arsenijevic, D., Onuma, H., Pecqueur, C., Raimbault, S., Manning, B.S., Miroux, B., Couplan, E., Alves-Guerra, M.C., Goubern, M., Surwit, R., et al. (2000). Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat. Genet. 26, 435-439.   DOI
2 Back, P., Braeckman, B.P., and Matthijssens, F. (2012). ROS in aging Caenorhabditis elegans: damage or signaling? Oxid. Med. Cell Longev. 2012, 608478.
3 Basu Ball, W., Kar, S., Mukherjee, M., Chande, A.G., Mukhopadhyaya, R., and Das, P.K. (2011). Uncoupling protein 2 negatively regulates mitochondrial reactive oxygen species generation and induces phosphatase-mediated anti-inflammatory response in experimental visceral leishmaniasis. J. Immunol. 187, 1322-1332.   DOI
4 Beckman, K.B., and Ames, B.N. (1998). The free radical theory of aging matures. Physiol. Rev. 78, 547-581.   DOI
5 Boveris, A., Oshino, N., and Chance, B. (1972). The cellular production of hydrogen peroxide. Biochem. J. 128, 617-630.   DOI
6 Brenner, S. (1974). The genetics of Caenorhabditis elegans. Genetics 77, 71-94.
7 Chan, C.B., MacDonald, P.E., Saleh, M.C., Johns, D.C., Marban, E., and Wheeler, M.B. (1999). Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets. Diabetes 48, 1482-1486.   DOI
8 Chavez, V., Mohri-Shiomi, A., Maadani, A., Vega, L.A., and Garsin, D.A. (2007). Oxidative stress enzymes are required for DAF-16-mediated immunity due to generation of reactive oxygen species by Caenorhabditis elegans. Genetics 176, 1567-1577.   DOI
9 Chen, C.H., Chen, Y.C., Jiang, H.C., Chen, C.K., and Pan, C.L. (2013). Neuronal aging: learning from C. elegans. J. Mol. Signal. 8, 14.   DOI
10 Cho, I., Hwang, G.J., and Cho, J.H. (2015). pxn-1 and pxn-2 May Interact Negatively during Neuronal Development and Aging in C. elegans. Mol. Cells 38, 729-733.   DOI
11 Deierborg, T., Wieloch, T., Diano, S., Warden, C.H., Horvath, T.L., and Mattiasson, G. (2008). Overexpression of UCP2 protects thalamic neurons following global ischemia in the mouse. J. Cereb. Blood Flow Metab. 28, 1186-1195.   DOI
12 Divakaruni, A.S., and Brand, M.D. (2011). The regulation and physiology of mitochondrial proton leak. Physiology (Bethesda) 26, 192-205.   DOI
13 Duan, W., and Mattson, M.P. (1999). Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. J. Neurosci. Res. 57, 195-206.   DOI
14 Echtay, K.S. (2007). Mitochondrial uncoupling proteins--what is their physiological role? Free Radic. Biol. Med. 43, 1351-1371.   DOI
15 Echtay, K.S., and Brand, M.D. (2007). 4-hydroxy-2-nonenal and uncoupling proteins: an approach for regulation of mitochondrial ROS production. Redox Rep. 12, 26-29.   DOI
16 Echtay, K.S., Murphy, M.P., Smith, R.A., Talbot, D.A., and Brand, M.D. (2002). Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J. Biol. Chem. 277, 47129-47135.   DOI
17 Echtay, K.S., Esteves, T.C., Pakay, J.L., Jekabsons, M.B., Lambert, A.J., Portero-Otin, M., Pamplona, R., Vidal-Puig, A.J., Wang, S., Roebuck, S.J., et al. (2003). A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J. 22, 4103-4110.   DOI
18 Erlanson-Albertsson, C. (2003). The role of uncoupling proteins in the regulation of metabolism. Acta. Physiol. Scand. 178, 405-412.   DOI
19 Farkas, D.L., Wei, M.D., Febbroriello, P., Carson, J.H., and Loew, L.M. (1989). Simultaneous imaging of cell and mitochondrial membrane potentials. Biophys. J. 56, 1053-1069.   DOI
20 Fahn, S., and Cohen, G. (1992). The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. Ann. Neurol. 32, 804-812.   DOI
21 Gates, A.C., Bernal-Mizrachi, C., Chinault, S.L., Feng, C., Schneider, J.G., Coleman, T., Malone, J.P., Townsend, R.R., Chakravarthy, M.V., and Semenkovich, C.F. (2007). Respiratory uncoupling in skeletal muscle delays death and diminishes agerelated disease. Cell Metab. 6, 497-505.   DOI
22 Haines, B., and Li, P.A. (2012). Overexpression of mitochondrial uncoupling protein 2 inhibits inflammatory cytokines and activates cell survival factors after cerebral ischemia. PLoS One 7, e31739.   DOI
23 Hansford, R.G., Hogue, B.A., and Mildaziene, V. (1997). Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age. J. Bioenerg. Biomembr. 29, 89-95.   DOI
24 Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298-300.   DOI
25 Harman, D. (1972). The biologic clock: the mitochondria? J. Am. Geriatr. Soc. 20, 145-147.   DOI
26 Harman, D. (2009). Origin and evolution of the free radical theory of aging: a brief personal history, 1954-2009. Biogerontology 10, 773-781.   DOI
27 Hekimi, S., Lapointe, J., and Wen, Y. (2011). Taking a "good" look at free radicals in the aging process. Trends Cell Biol. 21, 569-576.   DOI
28 Ji, C., Guo, W., Zhang, M., Lu, X., Ni, Y., and Guo, X. (2012). Caenorhabditis elegans ucp-4 regulates fat metabolism:suppression of ucp-4 expression induced obese phenotype and caused impairment of insulin like pathway. Gene 491, 158-164.   DOI
29 Hwang, A.B., Ryu, E.A., Artan, M., Chang, H.W., Kabir, M.H., Nam, H.J., Lee, D., Yang, J.S., Kim, S., Mair, W.B., et al. (2014). Feedback regulation via AMPK and HIF-1 mediates ROSdependent longevity in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 111, E4458-4467.   DOI
30 Iser, W.B., Kim, D., Bachman, E., and Wolkow, C. (2005). Examination of the requirement for ucp-4, a putative homolog of mammalian uncoupling proteins, for stress tolerance and longevity in C. elegans. Mech. Ageing Dev. 126, 1090-1096.   DOI
31 Kamath, R.S., Martinez-Campos, M., Zipperlen, P., Fraser, A.G., and Ahringer, J. (2001). Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol 2, 1-10.
32 Korshunov, S.S., Skulachev, V.P., and Starkov, A.A. (1997). High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 416, 15-18.   DOI
33 Koziel, A., Sobieraj, I., and Jarmuszkiewicz, W. (2015). Increased activity of mitochondrial uncoupling protein 2 improves stress resistance in cultured endothelial cells exposed in vitro to high glucose levels. Am. J. Physiol. Heart Circ. Physiol. 309, H147-156.   DOI
34 Lin, M.T., and Beal, M.F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787-795.   DOI
35 Loew, L.M., Tuft, R.A., Carrington, W., and Fay, F.S. (1993). Imaging in five dimensions: time-dependent membrane potentials in individual mitochondria. Biophys. J. 65, 2396-2407.   DOI
36 Murphy, M.P., Echtay, K.S., Blaikie, F.H., Asin-Cayuela, J., Cocheme, H.M., Green, K., Buckingham, J.A., Taylor, E.R., Hurrell, F., Hughes, G., et al. (2003). Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation: studies using a mitochondria-targeted spin trap derived from alpha-phenyl-N-tert-butylnitrone. J. Biol. Chem. 278, 48534-48545.   DOI
37 Mao, W., Yu, X.X., Zhong, A., Li, W., Brush, J., Sherwood, S.W., Adams, S.H., and Pan, G. (1999). UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett. 443, 326-330.   DOI
38 Mattiasson, G., and Sullivan, P.G. (2006). The emerging functions of UCP2 in health, disease, and therapeutics. Antioxid. Redox Signal. 8, 1-38.   DOI
39 Mello, C., and Fire, A. (1995). DNA transformation. Methods Cell Biol 48, 451-482.   DOI
40 Nicholls, D.G., and Locke, R.M. (1984). Thermogenic mechanisms in brown fat. Physiol. Rev. 64, 1-64.   DOI
41 Pan, C.L., Peng, C.Y., Chen, C.H., and McIntire, S. (2011). Genetic analysis of age-dependent defects of the Caenorhabditis elegans touch receptor neurons. Proc. Natl. Acad. Sci. USA 108, 9274-9279.   DOI
42 Pfeiffer, M., Kayzer, E.B., Yang, X., Abramson, E., Kenaston, M.A., Lago, C.U., Lo, H.H., Sedensky, M.M., Lunceford, A., Clarke, C.F., et al. (2011). Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport. J. Biol. Chem. 286, 37712-37720.   DOI
43 Sanchis, D., Fleury, C., Chomiki, N., Goubern, M., Huang, Q., Neverova, M., Gregoire, F., Easlick, J., Raimbault, S., Levi-Meyrueis, C., et al. (1998). BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast. J. Biol. Chem. 273, 34611-34615.   DOI
44 Tank, E.M., Rodgers, K.E., and Kenyon, C. (2011). Spontaneous age-related neurite branching in Caenorhabditis elegans. J. Neurosci. 31, 9279-9288.   DOI
45 Sohal, R.S., and Weindruch, R. (1996). Oxidative stress, caloric restriction, and aging. Science 273, 59-63.   DOI
46 Sullivan, P.G., Rippy, N.A., Dorenbos, K., Concepcion, R.C., Agarwal, A.K., and Rho, J.M. (2004). The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann. Neurol. 55, 576-580.   DOI
47 Talbot, D.A., Lambert, A.J., and Brand, M.D. (2004). Production of endogenous matrix superoxide from mitochondrial complex I leads to activation of uncoupling protein 3. FEBS Lett. 556, 111-115.   DOI
48 Toth, M.L., Melentijevic, I., Shah, L., Bhatia, A., Lu, K., Talwar, A., Naji, H., Ibanez-Ventoso, C., Ghose, P., Jevince, A., et al. (2012). Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system. J. Neurosci. 32, 8778-8790.   DOI
49 Votyakova, T.V., and Reynolds, I.J. (2001). DeltaPsi(m)-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. J. Neurochem. 79, 266-277.
50 Yang, J.S., Nam, H.J., Seo, M., Han, S.K., Choi, Y., Nam, H.G., Lee, S.J., and Kim, S. (2011). OASIS: online application for the survival analysis of lifespan assays performed in aging research. PLoS One 6, e23525.   DOI
51 Yoneda, T., Benedetti, C., Urano, F., Clark, S.G., Harding, H.P., and Ron, D. (2004). Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J. Cell Sci. 117, 4055-4066.   DOI
52 Yu, X.X., Mao, W., Zhong, A., Schow, P., Brush, J., Sherwood, S.W., Adams, S.H., and Pan, G. (2000). Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation. FASEB J. 14, 1611-1618.   DOI