CellBio  Vol.4 No.2 , June 2015
Mitochondrial Protein in the Nucleus
Abstract: Other than the respiratory chain components, most mitochondrial proteins are synthesized in the cytosol and imported into the mitochondria. Many mitochondrial proteins therefore have at least a transient cytosolic appearance, and several have a dual mitochondrial-cytosol functional localization. However, recent work has revealed several proteins, one of which is a large protein complex, with dual mitochondrial and nuclear localizations. The enzyme fumarase which catalyzes the reversible hydration/dehydration of fumarate to malate is part of the mitochondria matrix tricarboxylic acid (TCA) cycle. It could, however, be recruited from the cytosol to the nucleus in response to DNA damage, where it is important for DNA repair. The pyruvate dehydrogenase complex (PDC) generates acetyl-CoA from pyruvate, and is recently shown to translocate from the mitochondrial matrix into the nuclear under mitogenic and stress conditions to generate acetyl–CoA within the nucleus. The mitochondrial monooxygenase CLK-1/COQ7 responsible for the synthesis of ubiquinone is most recently found to have a nuclear isoform with an uncleaved amino terminus, where it affects transcriptional changes associated with mitochondrial reactive oxygen species (ROS) generation. In this review, we highlight these unusual cases of nuclear localization of classically mitochondrial proteins, and discuss their possible functions in the nucleus.
Cite this paper: Tang, B. (2015) Mitochondrial Protein in the Nucleus. CellBio, 4, 23-29. doi: 10.4236/cellbio.2015.42003.

[1]   Gray, M.W. (2012) Mitochondrial Evolution. Cold Spring Harbor Perspectives in Biology, 4, a011403.

[2]   Rehling, P., Brandner, K. and Pfanner, N. (2004) Mitochondrial Import and the Twin-Pore Translocase. Nature Reviews Molecular Cell Biology, 5, 519-530.

[3]   Dudek, J., Rehling, P. and van der Laan, M. (2013) Mitochondrial Protein Import: Common Principles and Physiological Networks. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1833, 274-285.

[4]   Qiu, J., Wenz, L.-S., Zerbes, R.M., et al. (2013) Coupling of Mitochondrial Import and Export Translocases by Receptor-Mediated Supercomplex Formation. Cell, 154, 596-608.

[5]   Yogev, O. and Pines, O. (2011) Dual Targeting of Mitochondrial Proteins: Mechanism, Regulation and Function. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1808, 1012-1020.

[6]   Terry, L.J. and Wente, S.R. (2009) Flexible Gates: Dynamic Topologies and Functions for FG Nucleoporins in Nucleocytoplasmic Transport. Eukaryotic Cell, 8, 1814-1827.

[7]   Tran, E.J., King, M.C. and Corbett, A.H. (2014) Macromolecular Transport between the Nucleus and the Cytoplasm: Advances in Mechanism and Emerging Links to Disease. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1843, 2784-2795.

[8]   Cautain, B., Hill, R., de Pedro, N. and Link, W. (2015) Components and Regulation of Nuclear Transport Processes. FEBS Journal, 282, 445-462.

[9]   Mor, A., White, M.A. and Fontoura, B.M.A. (2014) Nuclear Trafficking in Health and Disease. Current Opinion in Cell Biology, 28, 28-35.

[10]   Czypiorski, P., Altschmied, J., Rabanter, L.L., Goy, C., Jakob, S. and Haendeler, J. (2014) Outfielders Playing in the Infield: Functions of Aging-Associated “Nuclear” Proteins in the Mitochondria. Current Molecular Medicine, 14, 1247-1251.

[11]   Vaseva, A.V., Marchenko, N.D., Ji, K., Tsirka, S.E., Holzmann, S. and Moll, U.M. (2012) p53 Opens the Mitochondrial Permeability Transition Pore to Trigger Necrosis. Cell, 149, 1536-1548.

[12]   Yager, J.D. and Chen, J.Q. (2007) Mitochondrial Estrogen Receptors—New Insights into Specific Functions. Trends in Endocrinology and Metabolism, 18, 89-91.

[13]   Liang, J., Xie, Q., Li, P., Zhong, X. and Chen, Y. (2015) Mitochondrial Estrogen Receptor β Inhibits Cell Apoptosis via Interaction with Bad in a Ligand-Independent Manner. Molecular and Cellular Biochemistry, 401, 71-86.

[14]   Saretzki, G. (2009) Telomerase, Mitochondria and Oxidative Stress. Experimental Gerontology, 44, 485-492.

[15]   Haendeler, J., Dröse, S., Büchner, N., Jakob, S., Altschmied, J., Goy, C., Spyridopoulos, I., Zeiher, A.M., Brandt, U. and Dimmeler, S. (2009) Mitochondrial Telomerase Reverse Transcriptase Binds to and Protects Mitochondrial DNA and Function from Damage. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 929-935.

[16]   Ale-Agha, N., Dyballa-Rukes, N., Jakob, S., Altschmied, J. and Haendeler, J. (2014) Cellular Functions of the Dual-Targeted Catalytic Subunit of Telomerase, Telomerase Reverse Transcriptase—Potential Role in Senescence and Aging. Experimental Gerontology, 56, 189-193.

[17]   Meshkini, A. and Yazdanparast, R. (2012) Foxo3a Targets Mitochondria during Guanosine 5’-Triphosphate Guided Erythroid Differentiation. The International Journal of Biochemistry & Cell Biology, 44, 1718-1728.

[18]   Hagenbuchner, J. and Ausserlechner, M.J. (2013) Mitochondria and FOXO3: Breath or Die. Frontiers in Physiology, 4, 147.

[19]   Jacobs, K.M., Pennington, J.D., Bisht, K.S., Aykin-Burns, N., Kim, H.S., Mishra, M., Sun, L., Nguyen, P., Ahn, B.H., Leclerc, J., Deng, C.X., Spitz, D.R. and Gius, D. (2008) SIRT3 Interacts with the Daf-16 Homolog FoXO3a in the Mitochondria, as Well as Increases FOXO3a Dependent Gene Expression. International Journal of Biological Sciences, 4, 291-299.

[20]   Tang, B.L. (2006) SIRT1, Neuronal Cell Survival and the Insulin/IGF-1 Aging Paradox. Neurobiology of Aging, 27, 501-505.

[21]   Mouchiroud, L., Houtkooper, R.H., Moullan, N., Katsyuba, E., Ryu, D., Cantó, C., Mottis, A., Jo, Y.S., Viswanathan, M., Schoonjans, K., Guarente, L. and Auwerx, J. (2013) The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FoXO Signaling. Cell, 154, 430-441.

[22]   Motta, M.C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M. and Guarente, L. (2004) Mammalian SIRT1 Represses Forkhead Transcription Factors. Cell, 116, 551-563.

[23]   Olmos, Y., Sánchez-Gómez, F.J., Wild, B., García-Quintans, N., Cabezudo, S., Lamas, S. and Monsalve, M. (2013) SirT1 Regulation of Antioxidant Genes Is Dependent on the Formation of a FoxO3a/PGC-1α Complex. Antioxidants & Redox Signaling, 19, 1507-1521.

[24]   Aquilano, K., Vigilanza, P., Baldelli, S., Pagliei, B., Rotilio, G. and Ciriolo, M.R. (2010) Peroxisome Proliferator-Activated Receptor Gamma Co-Activator 1α (PGC-1α) and Sirtuin 1 (SIRT1) Reside in Mitochondria: Possible Direct Function in Mitochondrial Biogenesis. Journal of Biological Chemistry, 285, 21590-21599.

[25]   Yogev, O., Naamati, A. and Pines, O. (2011) Fumarase: A Paradigm of Dual Targeting and Dual Localized Functions. FEBS Journal, 278, 4230-4242.

[26]   Yogev, O., Yogev, O., Singer, E., Shaulian, E., Goldberg, M., Fox, T.D. and Pines, O. (2010) Fumarase: A Mitochondrial Metabolic Enzyme and a Cytosolic/Nuclear Component of the DNA Damage Response. PLoS Biology, 8, e1000328.

[27]   Tomlinson, I.P.M., Rowan, A.J., Barclay, E., et al. (2002) Germline Mutations in FH Predispose to Dominantly Inherited Uterine Fibroids, Skin Leiomyomata and Papillary Renal Cell Cancer. Nature Genetics, 30, 406-410.

[28]   Isaacs, J.S., Jung, Y.J., Mole, D.R., Lee, S., Torres-Cabala, C., Chung, Y.L., Merino, M., Trepel, J., Zbar, B., Toro, J., Ratcliffe, P.J., Linehan, W.M. and Neckers, L. (2005) HIF Overexpression Correlates with Biallelic Loss of Fumarate Hydratase in Renal Cancer: Novel Role of Fumarate in Regulation of HIF Stability. Cancer Cell, 8, 143-153.

[29]   Patel, M.S. and Korotchkina, L.G. (2006) Regulation of the Pyruvate Dehydrogenase Complex. Biochemical Society Transactions, 34, 217-222.

[30]   Tang, B. (2014) The Mitochondrial Pyruvate Carrier and Metabolic Regulation. Cell Biology, 3, 111-117.

[31]   Zhou, Z.H., Liao, W., Cheng, R.H., Lawson, J.E., McCarthy, D.B., Reed, L.J. and Stoops, J.K. (2001) Direct Evidence for the Size and Con-formational Variability of the Pyruvate Dehydrogenase Complex Revealed by Three-Dimensional Electron Microscopy. The “Breathing” Core and Its Functional Relationship to Protein Dynamics. The Journal of Biological Chemistry, 276, 21704-21713.

[32]   Sutendra, G., Kinnaird, A., Dromparis, P., Paulin, R., Stenson, T.H., Haromy, A., Hashimoto, K., Zhang, N., Flaim, E. and Michelakis, E.D. (2014) A nuclear Pyruvate Dehydrogenase Complex Is Important for the Generation of Acetyl-CoA and Histone Acetylation. Cell, 158, 84-97.

[33]   Chueh, F.Y., Leong, K.F., Cronk, R.J., Venkitachalam, S., Pabich, S. and Yu, C.L. (2011) Nuclear Localization of Pyruvate Dehydrogenase Complex-E2 (PDC-E2), a Mitochondrial Enzyme, and Its Role in Signal Transducer and Activator of Transcription 5 (STAT5)-Dependent Gene Transcription. Cellular Signalling, 23, 1170-1178.

[34]   Hitosugi, T., Fan, J., Chung, T.W., Lythgoe, K., Wang, X., Xie, J., Ge, Q., Gu, T.L., Polakiewicz, R.D., Roesel, J.L., Chen, G.Z., Boggon, T.J., Lonial, S., Fu, H., Khuri, F.R., Kang, S. and Chen, J. (2011) Tyrosine Phosphorylation of Mitochondrial Pyruvate Dehydrogenase Kinase 1 Is Important for Cancer Metabolism. Molecular Cell, 44, 864-877.

[35]   Wellen, K.E., Hatzivassiliou, G., Sachdeva, U.M., Bui, T.V., Cross, J.R. and Thompson, C.B. (2009) ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation. Science, 324, 1076-1080.

[36]   Rea, S. (2001) CLK-1/Coq7p Is a DMQ Mono-Oxygenase and a New Member of the Di-Iron Carboxylate Protein Family. FEBS Letters, 509, 389-394.

[37]   Vajo, Z., King, L.M., Jonassen, T., Wilkin, D.J., Ho, N., Munnich, A., Clarke, C.F. and Francomano, C.A. (1999) Conservation of the Caenorhabditis elegans Timing Gene CLK-1 from Yeast to Human: A Gene Required for Ubiquinone Biosynthesis with potential Implications for Aging. Mammalian Genome, 10, 1000-1004.

[38]   Lakowski, B. and Hekimi, S. (1996) Determination of Life-Span in Caenorhabditis elegans by Four Clock Genes. Science, 272, 1010-1013.

[39]   Takahashi, K., Noda, Y., Ohsawa, I., Shirasawa, T. and Takahashi, M. (2014) Extended Lifespan, Reduced Body Size and Leg Skeletal Muscle Mass, and Decreased Mitochondrial Function in CLK-1 Transgenic Mice. Experimental Gerontology, 58, 146-153.

[40]   Monaghan, R.M., Barnes, R.G., Fisher, K., Andreou, T., Rooney, N., Poulin, G.B. and Whitmarsh, A.J. (2015) A Nuclear Role for the Respiratory Enzyme CLK-1 in Regulating Mitochondrial Stress Responses and Longevity. Nature Cell Biology, 17, 782-792.

[41]   Jovaisaite, V., Mouchiroud, L. and Auwerx, J. (2014) The Mitochondrial Unfolded Protein Response, a Conserved Stress Response Pathway with Implications in Health and Disease. The Journal of Experimental Biology, 217, 137-143.

[42]   Schulz, A.M. and Haynes, C.M. (2015) UPRmt-Mediated Cytoprotection and Organismal Aging. Biochimica et Biophysica Acta (BBA)-Bioenergetics, in press.

[43]   Ng, F. and Tang, B.L. (2014) Pyruvate Dehydrogenase Complex (PDC) Export from the Mitochondrial Matrix. Molecular Membrane Biology, 31, 207-210.

[44]   Nargund, A.M., Pellegrino, M.W., Fiorese, C.J., Baker, B.M. and Haynes, C.M. (2012) Mitochondrial Import Efficiency of ATFS-1 Regulates Mitochondrial UPR Activation. Science, 337, 587-590.

[45]   Nargund, A.M., Fiorese, C.J., Pellegrino, M.W., Deng, P. and Haynes, C.M. (2015) Mitochondrial and Nuclear Accumulation of the Transcription Factor ATFS-1 Promotes OXPHOS Recovery during the UPRmt. Molecular Cell, 58, 123-133.

[46]   Naamati, A., Regev-Rudzki, N., Galperin, S., Lill, R. and Pines, O. (2009) Dual Targeting of Nfs1 and Discovery of Its Novel Processing Enzyme, Icp55. The Journal of Biological Chemistry, 284, 30200-30208.

[47]   Marelja, Z., Mullick Chowdhury, M., Dosche, C., Hille, C., Baumann, O., Löhmannsröben, H.G. and Leimkühler, S. (2013) The L-Cysteine Desulfurase NFS1 Is Localized in the Cytosol Where It Provides the Sulfur for Molybdenum Cofactor Biosynthesis in Humans. PLoS ONE, 8, e60869.

[48]   Nakai, Y., Nakai, M., Hayashi, H. and Kagamiyama, H. (2001) Nuclear Localization of Yeast Nfs1p Is Required for Cell Survival. The Journal of Biological Chemistry, 276, 8314-8320.