中文摘要
粒線體呼吸鏈第一酵素複合體對於能量產生是非常重要的。其中的次單元NADH
dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7) 具有高度保留性並含有第一酵素複合體
最後一個鐵硫中心N2。NDUFS7 為一個由細胞核轉錄後在細胞質轉譯的蛋白並藉由粒線體標
的序列(mitochondrial targeting sequence, MTS)進入粒線體。除此之外，在靠近NDUFS7Ｃ端
的位置上帶有核導出訊號(nuclear export signal, NES)及核導入訊號(nuclear localization signal,
NLS)。類小泛素化(SUMOylation)是指目標蛋白被類小泛素(small ubiquitin-like modifier,
SUMO)進行可逆性的修飾且被認為在調控細胞內反應上扮演關鍵性的角色。在先前的研究，
我們已經探討了SUMO1 對於NDUFS7 的修飾及其重要性。在本次的研究，我們進一步探討
其他旁系(paralogue)的類小泛素蛋白SUMO3 對於NDUFS7 的修飾及功能。為了找出主要類
小泛素化的位置，我們將SUMO3 上第11 號位置的離氨酸(Lysine)突變成精氨酸(Arginine)使
其只能形成單一SUMO3 的鍵結但無法形成多個SUMO3 鍵結的長鏈，我們也將NDUFS7 上
僅有可能與SUMO3形成鍵結的七個Lysine 及經預測最有可能形成非共價SUMO交互作用區
域(SUMO-interacting motif, SIM)各別突變進行觀察。根據突變分析的結果，沒有任何一種上
述建構的突變可以完全消除NDUFS7被SUMOylatiton 的現象。因此，NDUFS7的SUMOylation
可能同時有多個Lysine 及SIM 的參與。另外，透過NDUFS7 與SUMO3 的融合蛋白
(NDUFS7_SUMO3AA fusion protein)顯示與SUMO1 修飾相反的結果: SUMO3 的修飾會促進
NDUFS7 進入粒線體內且幾乎不會出現在核內。SUMO3 修飾對於NDUFS7 的生理意義也利
用給予不同的條件例如：破壞粒線體的膜電位、誘發細胞凋亡、缺氧、氧化壓力以及飢餓狀
態進行探討。更進一步地，我們發現SUMO3 對NDUFS7 的修飾在氯化鈷(CoCl2)誘發的缺氧
狀態會上升但在二氧化二氫(H2O2)誘導的氧化壓力時會下降。更詳細有關SUMOylation 如何
影響NDUFS7 在胞內的移動及其生理意義值得更進一步的研究。

Mitochondrial respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for energy
production. Human NADH dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7) is a
well-conserved subunit and contains an iron-sulfur cluster N2 (4Fe-4S tetranuclear) as the finial
electron transport center in complex I. As a nuclear-encoded protein and translated in cytosol, we
previously demonstrated NDUFS7 is imported into mitochondria by a mitochondrial targeting
sequence (MTS). In addition, we also identified that NDUFS7 possesses a nuclear export signal
(NES) and a nuclear localization signal (NLS) near the C-terminus. SUMOylation, the process of
protein conjugation with a small ubiquitin-like modifier (SUMO), is one type of reversible
modification and has been considered to play a key role in modulating many important cellular
processes. In previous studies, we have shown that NDUFS7 could be modified by SUMO1 and the
importance of this modification has been discussed. In this study, we tried to explore other
involvement of SUMO3, another SUMO paralogue, in NDUFS7 modification and function. To
map the major SUMOylation sites, we first mutated the lysine residue at position 11 on SUMO3 to
arginine, which was used to study the mono-SUMOylation and abolished the poly-SUMOylated
chain. We also constructed a series of NDUFS7 mutants with mutation(s) at seven lysine residues
or removing the predicated SUMO-interacting motif (SIM). According to the result of
mutation-scanning analyses, SUMOylation of NDUFS7 couldn’t be fully abolished in any of the
mutant construct. Therefore, multiple lysine residues and SIMs might be involved in the
SUMOylation of NDUFS7. In addition, the change of NDUFS7 translocation was observed in
NDUFS7_SUMO3AA fusion protein. In contrast to SUMO1 modification, NDUFS7 conjugation
with SUMO3 facilitated the import of NDUFS7 into mitochondria and nearly not in the nucleus.
The biological meaning of NDUFS7 modification with SUMO3 was investigated by introducing
various treatments such as dissipation of mitochondrial membrane potential, etoposide-induced
III
apoptosis, hypoxia, oxidative stress and deprivation of nutrition, respectively. Among them, we
uncovered that SUMOylation of NDUFS7 with SUMO3 was up-regulated in the CoCl2-induced
hypoxia condition but down-regulated under H2O2-triggered oxidative stress. The detailed
mechanism about how SUMOylation influences NDUFS7 subcellular localization and its
contribution to physiologic consequences deserves further exploration.

1. Martin, W., and Mentel, M. (2010) The origin of mitochondria. Nature Education 3, 58
2. Harbauer, A. B., Zahedi, R. P., Sickmann, A., Pfanner, N., and Meisinger, C. (2014) The
protein import machinery of mitochondria-a regulatory hub in metabolism, stress, and
disease. Cell metabolism 19, 357-372
3. Cagin, U., and Enriquez, J. A. (2015) The complex crosstalk between mitochondria and the
nucleus: What goes in between? The international journal of biochemistry & cell biology 63,
10-15
4. Yun, J., and Finkel, T. (2014) Mitohormesis. Cell metabolism 19, 757-766
5. Shadel, G. S., and Horvath, T. L. (2015) Mitochondrial ROS signaling in organismal
homeostasis. Cell 163, 560-569
6. Neupert, W., and Herrmann, J. M. (2007) Translocation of proteins into mitochondria.
Annual review of biochemistry 76, 723-749
7. Chacinska, A., Koehler, C. M., Milenkovic, D., Lithgow, T., and Pfanner, N. (2009)
Importing mitochondrial proteins: machineries and mechanisms. Cell 138, 628-644
8. Geissler, A., Krimmer, T., Bomer, U., Guiard, B., Rassow, J., and Pfanner, N. (2000)
Membrane potential-driven protein import into mitochondria. The sorting sequence of
cytochrome b(2) modulates the deltapsi-dependence of translocation of the matrix-targeting
sequence. Molecular biology of the cell 11, 3977-3991
9. Shiota, T., Mabuchi, H., Tanaka-Yamano, S., Yamano, K., and Endo, T. (2011) In vivo
protein-interaction mapping of a mitochondrial translocator protein Tom22 at work.
Proceedings of the National Academy of Sciences of the United States of America 108,
15179-15183
10. Omura, T. (1998) Mitochondria-targeting sequence, a multi-role sorting sequence
recognized at all steps of protein import into mitochondria. Journal of biochemistry 123,
1010-1016
11. Chandel, N. S. (2014) Mitochondria as signaling organelles. BMC biology 12, 34
12. Kotiadis, V. N., Duchen, M. R., and Osellame, L. D. (2014) Mitochondrial quality control
and communications with the nucleus are important in maintaining mitochondrial function
and cell health. Biochimica et biophysica acta 1840, 1254-1265
13. Yogev, O., and Pines, O. (2011) Dual targeting of mitochondrial proteins: mechanism,
regulation and function. Biochimica et biophysica acta 1808, 1012-1020
14. Regev-Rudzki, N., and Pines, O. (2007) Eclipsed distribution: a phenomenon of dual
targeting of protein and its significance. BioEssays : news and reviews in molecular,
cellular and developmental biology 29, 772-782
15. Monaghan, R. M., and Whitmarsh, A. J. (2015) Mitochondrial proteins moonlighting in the
71
nucleus. Trends in biochemical sciences 40, 728-735
16. 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 (New York, N.Y.) 337, 587-590
17. 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
18. 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
19. Ahmed, S., Passos, J. F., Birket, M. J., Beckmann, T., Brings, S., Peters, H., Birch-Machin,
M. A., von Zglinicki, T., and Saretzki, G. (2008) Telomerase does not counteract telomere
shortening but protects mitochondrial function under oxidative stress. Journal of cell
science 121, 1046-1053
20. Chen, L. Y., Zhang, Y., Zhang, Q., Li, H., Luo, Z., Fang, H., Kim, S. H., Qin, L., Yotnda, P.,
Xu, J., Tu, B. P., Bai, Y., and Songyang, Z. (2012) Mitochondrial localization of telomeric
protein TIN2 links telomere regulation to metabolic control. Molecular cell 47, 839-850
21. Chi, Z., Nie, L., Peng, Z., Yang, Q., Yang, K., Tao, J., Mi, Y., Fang, X., Balajee, A. S., and
Zhao, Y. (2012) RecQL4 cytoplasmic localization: implications in mitochondrial DNA
oxidative damage repair. The international journal of biochemistry & cell biology 44,
1942-1951
22. Croteau, D. L., Rossi, M. L., Canugovi, C., Tian, J., Sykora, P., Ramamoorthy, M., Wang, Z.
M., Singh, D. K., Akbari, M., Kasiviswanathan, R., Copeland, W. C., and Bohr, V. A. (2012)
RECQL4 localizes to mitochondria and preserves mitochondrial DNA integrity. Aging cell
11, 456-466
23. Yogev, O., Naamati, A., and Pines, O. (2011) Fumarase: a paradigm of dual targeting and
dual localized functions. The FEBS journal 278, 4230-4242
24. Forkink, M., Manjeri, G. R., Liemburg-Apers, D. C., Nibbeling, E., Blanchard, M., Wojtala,
A., Smeitink, J. A., Wieckowski, M. R., Willems, P. H., and Koopman, W. J. (2014)
Mitochondrial hyperpolarization during chronic complex I inhibition is sustained by low
activity of complex II, III, IV and V. Biochimica et biophysica acta 1837, 1247-1256
25. Sazanov, L. A. (2015) A giant molecular proton pump: structure and mechanism of
respiratory complex I. Nature reviews. Molecular cell biology 16, 375-388
26. Smeitink, J., van den Heuvel, L., and DiMauro, S. (2001) The genetics and pathology of
oxidative phosphorylation. Nature reviews. Genetics 2, 342-352
27. Hatefi, Y., Haavik, A. G., and Griffiths, D. E. (1962) Studies on the electron transfer system.
XL. Preparation and properties of mitochondrial DPNH-coenzyme Q reductase. The
Journal of biological chemistry 237, 1676-1680
72
28. Acín-Pérez, R., Fernández-Silva, P., Peleato, M. L., Pérez-Martos, A., and Enriquez, J. A.
(2008) Respiratory active mitochondrial supercomplexes. Molecular cell 32, 529-539
29. Vartak, R., Porras, C. A., and Bai, Y. (2013) Respiratory supercomplexes: structure,
function and assembly. Protein & cell 4, 582-590
30. Maranzana, E., Barbero, G., Falasca, A. I., Lenaz, G., and Genova, M. L. (2013)
Mitochondrial respiratory supercomplex association limits production of reactive oxygen
species from complex I. Antioxidants & redox signaling 19, 1469-1480
31. Vinothkumar, K. R., Zhu, J., and Hirst, J. (2014) Architecture of mammalian respiratory
complex I. Nature 515, 80-84
32. Janssen, R. J., Nijtmans, L. G., van den Heuvel, L. P., and Smeitink, J. A. (2006)
Mitochondrial complex I: structure, function and pathology. Journal of inherited metabolic
disease 29, 499-515
33. Brandt, U. (2006) Energy converting NADH:quinone oxidoreductase (complex I). Annual
review of biochemistry 75, 69-92
34. Sazanov, L. A., and Hinchliffe, P. (2006) Structure of the hydrophilic domain of respiratory
complex I from Thermus thermophilus. Science (New York, N.Y.) 311, 1430-1436
35. Hyslop, S. J., Duncan, A. M., Pitkanen, S., and Robinson, B. H. (1996) Assignment of the
PSST subunit gene of human mitochondrial complex I to chromosome 19p13. Genomics 37,
375-380
36. Hirst, J. (2013) Mitochondrial complex I. Annual review of biochemistry 82, 551-575
37. Hirst, J., Carroll, J., Fearnley, I. M., Shannon, R. J., and Walker, J. E. (2003) The nuclear
encoded subunits of complex I from bovine heart mitochondria. Biochimica et biophysica
acta 1604, 135-150
38. Leigh, D. (1951) Subacute necrotizing encephalomyelopathy in an infant. Journal of
neurology, neurosurgery, and psychiatry 14, 216
39. Triepels, R. H., van den Heuvel, L. P., Loeffen, J. L., Buskens, C. A., Smeets, R. J., Rubio
Gozalbo, M. E., Budde, S. M., Mariman, E. C., Wijburg, F. A., Barth, P. G., Trijbels, J. M.,
and Smeitink, J. A. (1999) Leigh syndrome associated with a mutation in the NDUFS7
(PSST) nuclear encoded subunit of complex I. Annals of neurology 45, 787-790
40. Andreazza, A. C., Wang, J. F., Salmasi, F., Shao, L., and Young, L. T. (2013) Specific
subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar
disorder. Journal of neurochemistry 127, 552-561
41. Andreazza, A. C., Shao, L., Wang, J. F., and Young, L. T. (2010) Mitochondrial complex I
activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients
with bipolar disorder. Archives of general psychiatry 67, 360-368
42. Frykman, S., Teranishi, Y., Hur, J. Y., Sandebring, A., Yamamoto, N. G., Ancarcrona, M.,
Nishimura, T., Winblad, B., Bogdanovic, N., Schedin-Weiss, S., Kihara, T., and Tjernberg,
L. O. (2012) Identification of two novel synaptic gamma-secretase associated proteins that
affect amyloid beta-peptide levels without altering Notch processing. Neurochemistry
73
international 61, 108-118
43. Meluh, P. B., and Koshland, D. (1995) Evidence that the MIF2 gene of Saccharomyces
cerevisiae encodes a centromere protein with homology to the mammalian centromere
protein CENP-C. Molecular biology of the cell 6, 793-807
44. Shen, Z., Pardington-Purtymun, P. E., Comeaux, J. C., Moyzis, R. K., and Chen, D. J. (1996)
UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins.
Genomics 36, 271-279
45. Okura, T., Gong, L., Kamitani, T., Wada, T., Okura, I., Wei, C. F., Chang, H. M., and Yeh,
E. T. (1996) Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death
by a novel protein, sentrin. Journal of immunology (Baltimore, Md. : 1950) 157, 4277-4281
46. Boddy, M. N., Howe, K., Etkin, L. D., Solomon, E., and Freemont, P. S. (1996) PIC 1, a
novel ubiquitin-like protein which interacts with the PML component of a multiprotein
complex that is disrupted in acute promyelocytic leukaemia. Oncogene 13, 971-982
47. Mahajan, R., Delphin, C., Guan, T., Gerace, L., and Melchior, F. (1997) A small
ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex
protein RanBP2. Cell 88, 97-107
48. Wilson, V. G. (2009) SUMO Regulation of Cellular Processes,
49. Flotho, A., and Melchior, F. (2013) Sumoylation: a regulatory protein modification in
health and disease. Annual review of biochemistry 82, 357-385
50. Guo, D., Han, J., Adam, B. L., Colburn, N. H., Wang, M. H., Dong, Z., Eizirik, D. L., She, J.
X., and Wang, C. Y. (2005) Proteomic analysis of SUMO4 substrates in HEK293 cells
under serum starvation-induced stress. Biochemical and biophysical research
communications 337, 1308-1318
51. Wei, W., Yang, P., Pang, J., Zhang, S., Wang, Y., Wang, M. H., Dong, Z., She, J. X., and
Wang, C. Y. (2008) A stress-dependent SUMO4 sumoylation of its substrate proteins.
Biochemical and biophysical research communications 375, 454-459
52. Xu, Z., and Au, S. W. (2005) Mapping residues of SUMO precursors essential in
differential maturation by SUMO-specific protease, SENP1. The Biochemical journal 386,
325-330
53. Hickey, C. M., Wilson, N. R., and Hochstrasser, M. (2012) Function and regulation of
SUMO proteases. Nature reviews. Molecular cell biology 13, 755-766
54. Gareau, J. R., and Lima, C. D. (2010) The SUMO pathway: emerging mechanisms that
shape specificity, conjugation and recognition. Nature reviews. Molecular cell biology 11,
861-871
55. Tatham, M. H., Jaffray, E., Vaughan, O. A., Desterro, J. M., Botting, C. H., Naismith, J. H.,
and Hay, R. T. (2001) Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein
substrates by SAE1/SAE2 and Ubc9. The Journal of biological chemistry 276,
35368-35374
56. Denuc, A., and Marfany, G. (2010) SUMO and ubiquitin paths converge. Biochemical
74
Society transactions 38, 34-39
57. Matic, I., van Hagen, M., Schimmel, J., Macek, B., Ogg, S. C., Tatham, M. H., Hay, R. T.,
Lamond, A. I., Mann, M., and Vertegaal, A. C. (2008) In vivo identification of human small
ubiquitin-like modifier polymerization sites by high accuracy mass spectrometry and an in
vitro to in vivo strategy. Molecular & cellular proteomics : MCP 7, 132-144
58. Rodriguez, M. S., Dargemont, C., and Hay, R. T. (2001) SUMO-1 conjugation in vivo
requires both a consensus modification motif and nuclear targeting. The Journal of
biological chemistry 276, 12654-12659
59. Hietakangas, V., Anckar, J., Blomster, H. A., Fujimoto, M., Palvimo, J. J., Nakai, A., and
Sistonen, L. (2006) PDSM, a motif for phosphorylation-dependent SUMO modification.
Proceedings of the National Academy of Sciences of the United States of America 103,
45-50
60. Yang, S. H., Galanis, A., Witty, J., and Sharrocks, A. D. (2006) An extended consensus
motif enhances the specificity of substrate modification by SUMO. The EMBO journal 25,
5083-5093
61. Matic, I., Schimmel, J., Hendriks, I. A., van Santen, M. A., van de Rijke, F., van Dam, H.,
Gnad, F., Mann, M., and Vertegaal, A. C. O. (2010) Site-specific identification of SUMO-2
targets in cells reveals an inverted SUMOylation motif and a hydrophobic cluster
SUMOylation motif. Molecular cell 39, 641-652
62. Picard, N., Caron, V., Bilodeau, S., Sanchez, M., Mascle, X., Aubry, M., and Tremblay, A.
(2012) Identification of estrogen receptor beta as a SUMO-1 target reveals a novel
phosphorylated sumoylation motif and regulation by glycogen synthase kinase 3beta.
Molecular and cellular biology 32, 2709-2721
63. Kerscher, O. (2007) SUMO junction-what's your function? New insights through
SUMO-interacting motifs. EMBO reports 8, 550-555
64. Droescher, M., Chaugule, V. K., and Pichler, A. (2013) SUMO rules: regulatory concepts
and their implication in neurologic functions. Neuromolecular medicine 15, 639-660
65. Wilkinson, K. A., and Henley, J. M. (2010) Mechanisms, regulation and consequences of
protein SUMOylation. The Biochemical journal 428, 133-145
66. Wang, L., Ma, Q., Yang, W., Mackensen, G. B., and Paschen, W. (2012) Moderate
hypothermia induces marked increase in levels and nuclear accumulation of
SUMO2/3-conjugated proteins in neurons. Journal of neurochemistry 123, 349-359
67. Guo, C., and Henley, J. M. (2014) Wrestling with stress: roles of protein SUMOylation and
deSUMOylation in cell stress response. IUBMB life 66, 71-77
68. Saitoh, H., and Hinchey, J. (2000) Functional heterogeneity of small ubiquitin-related
protein modifiers SUMO-1 versus SUMO-2/3. The Journal of biological chemistry 275,
6252-6258
69. Wood, L. D., Irvin, B. J., Nucifora, G., Luce, K. S., and Hiebert, S. W. (2003) Small
ubiquitin-like modifier conjugation regulates nuclear export of TEL, a putative tumor
75
suppressor. Proceedings of the National Academy of Sciences of the United States of
America 100, 3257-3262
70. Xia, P., Wang, S., Xiong, Z., Ye, B., Huang, L. Y., Han, Z. G., and Fan, Z. (2015) IRTKS
negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS
degradation. Nature communications 6, 8132
71. Tempe, D., Piechaczyk, M., and Bossis, G. (2008) SUMO under stress. Biochemical Society
transactions 36, 874-878
72. Huang, T. T., Wuerzberger-Davis, S. M., Wu, Z. H., and Miyamoto, S. (2003) Sequential
modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB
activation by genotoxic stress. Cell 115, 565-576
73. Bassi, C., Ho, J., Srikumar, T., Dowling, R. J. O., Gorrini, C., Miller, S. J., Mak, T. W.,
Neel, B. G., Raught, B., and Stambolic, V. (2013) Nuclear PTEN controls DNA repair and
sensitivity to genotoxic stress. Science (New York, N.Y.) 341, 395-399
74. Watts, F. Z. (2006) Sumoylation of PCNA: Wrestling with recombination at stalled
replication forks. DNA repair 5, 399-403
75. Kolesar, P., Sarangi, P., Altmannova, V., Zhao, X., and Krejci, L. (2012) Dual roles of the
SUMO-interacting motif in the regulation of Srs2 sumoylation. Nucleic acids research 40,
7831-7843
76. Enserink, J. M. (2015) Sumo and the cellular stress response. Cell division 10, 4
77. Sahin, U., Ferhi, O., Jeanne, M., Benhenda, S., Berthier, C., Jollivet, F., Niwa-Kawakita, M.,
Faklaris, O., Setterblad, N., de The, H., and Lallemand-Breitenbach, V. (2014) Oxidative
stress-induced assembly of PML nuclear bodies controls sumoylation of partner proteins.
The Journal of cell biology 204, 931-945
78. Bossis, G., Malnou, C. E., Farras, R., Andermarcher, E., Hipskind, R., Rodriguez, M.,
Schmidt, D., Muller, S., Jariel-Encontre, I., and Piechaczyk, M. (2005) Down-regulation of
c-Fos/c-Jun AP-1 dimer activity by sumoylation. Molecular and cellular biology 25,
6964-6979
79. Feligioni, M., and Nistico, R. (2013) SUMO: a (oxidative) stressed protein. Neuromolecular
medicine 15, 707-719
80. Gius, D., Botero, A., Shah, S., and Curry, H. A. (1999) Intracellular oxidation/reduction
status in the regulation of transcription factors NF-kappaB and AP-1. Toxicology letters 106,
93-106
81. Shim, H. S., Wei, M., Brandhorst, S., and Longo, V. D. (2015) Starvation promotes REV1
SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells.
Cancer research 75, 1056-1067
82. Lee, J., Yang, D. J., Lee, S., Hammer, G. D., Kim, K. W., and Elmquist, J. K. (2016)
Nutritional conditions regulate transcriptional activity of SF-1 by controlling sumoylation
and ubiquitination. Scientific reports 6
83. Bae, S.-H., Jeong, J.-W., Park, J. A., Kim, S.-H., Bae, M.-K., Choi, S.-J., and Kim, K.-W.
76
(2004) Sumoylation increases HIF-1α stability and its transcriptional activity. Biochemical
and biophysical research communications 324, 394-400
84. Berta, M. A., Mazure, N., Hattab, M., Pouysségur, J., and Brahimi-Horn, M. C. (2007)
SUMOylation of hypoxia-inducible factor-1α reduces its transcriptional activity.
Biochemical and biophysical research communications 360, 646-652
85. Nunez-O'Mara, A., Gerpe-Pita, A., Pozo, S., Carlevaris, O., Urzelai, B., Lopitz-Otsoa, F.,
Rodriguez, M. S., and Berra, E. (2015) PHD3-SUMO conjugation represses HIF1
transcriptional activity independently of PHD3 catalytic activity. Journal of cell science 128,
40-49
86. Wang, J., Wang, Y., and Lu, L. (2012) De-SUMOylation of CCCTC binding factor (CTCF)
in hypoxic stress-induced human corneal epithelial cells. The Journal of biological
chemistry 287, 12469-12479
87. Chen, H., and Chan, D. C. (2005) Emerging functions of mammalian mitochondrial fusion
and fission. Human molecular genetics 14, R283-R289
88. Figueroa-Romero, C., Iñiguez-Lluhí, J. A., Stadler, J., Chang, C.-R., Arnoult, D., Keller, P.
J., Hong, Y., Blackstone, C., and Feldman, E. L. (2009) SUMOylation of the mitochondrial
fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is
linked to its activity cycle. The FASEB Journal 23, 3917-3927
89. Frank, S., Gaume, B., Bergmann-Leitner, E. S., Leitner, W. W., Robert, E. G., Catez, F.,
Smith, C. L., and Youle, R. J. (2001) The role of dynamin-related protein 1, a mediator of
mitochondrial fission, in apoptosis. Developmental cell 1, 515-525
90. Wasiak, S., Zunino, R., and McBride, H. M. (2007) Bax/Bak promote sumoylation of DRP1
and its stable association with mitochondria during apoptotic cell death. The Journal of cell
biology 177, 439-450
91. Prudent, J., Zunino, R., Sugiura, A., Mattie, S., Shore, G. C., and McBride, H. M. (2015)
MAPL SUMOylation of Drp1 Stabilizes an ER/Mitochondrial Platform Required for Cell
Death. Molecular cell 59, 941-955
92. Zhu, S., and Matunis, M. J. (2009) Characterization of the effects and functions of
sumoylation through rapamycin-mediated heterodimerization. Methods in molecular
biology (Clifton, N.J.) 497, 153-164
93. Sohn, S. Y., and Hearing, P. (2016) The adenovirus E4-ORF3 protein functions as a SUMO
E3 ligase for TIF-1gamma sumoylation and poly-SUMO chain elongation. Proceedings of
the National Academy of Sciences of the United States of America
94. Berndt, A., Hofmann-Winkler, H., Tavalai, N., Hahn, G., and Stamminger, T. (2009)
Importance of covalent and noncovalent SUMO interactions with the major human
cytomegalovirus transactivator IE2p86 for viral infection. Journal of virology 83,
12881-12894
95. Liu, Y. C., Lin, M. C., Chen, H. C., Tam, M. F., and Lin, L. Y. (2011) The role of small
ubiquitin-like modifier-interacting motif in the assembly and regulation of metal-responsive
77
transcription factor 1. The Journal of biological chemistry 286, 42818-42829
96. Song, J., Durrin, L. K., Wilkinson, T. A., Krontiris, T. G., and Chen, Y. (2004)
Identification of a SUMO-binding motif that recognizes SUMO-modified proteins.
Proceedings of the National Academy of Sciences of the United States of America 101,
14373-14378
97. Carroll, J., Fearnley, I. M., Shannon, R. J., Hirst, J., and Walker, J. E. (2003) Analysis of the
subunit composition of complex I from bovine heart mitochondria. Molecular & Cellular
Proteomics 2, 117-126
98. Panse, V. G., Kressler, D., Pauli, A., Petfalski, E., Gnadig, M., Tollervey, D., and Hurt, E.
(2006) Formation and nuclear export of preribosomes are functionally linked to the
small-ubiquitin-related modifier pathway. Traffic (Copenhagen, Denmark) 7, 1311-1321
99. Finkbeiner, E., Haindl, M., and Muller, S. (2011) The SUMO system controls nucleolar
partitioning of a novel mammalian ribosome biogenesis complex. The EMBO journal 30,
1067-1078
100. Petrungaro, C., and Riemer, J. (2014) Mechanisms and physiological impact of the dual
localization of mitochondrial intermembrane space proteins. Biochemical Society
transactions 42, 952-958
101. Park, J. H., Lee, S. W., Yang, S. W., Yoo, H. M., Park, J. M., Seong, M. W., Ka, S. H., Oh,
K. H., Jeon, Y. J., and Chung, C. H. (2014) Modification of DBC1 by SUMO2/3 is crucial
for p53-mediated apoptosis in response to DNA damage. Nature communications 5
102. Harder, Z., Zunino, R., and McBride, H. (2004) Sumo1 conjugates mitochondrial substrates
and participates in mitochondrial fission. Current Biology 14, 340-345
103. Halliwell, B. (2007) Oxidative stress and cancer: have we moved forward? Biochemical
Journal 401, 1-11
104. Forkink, M., Basit, F., Teixeira, J., Swarts, H. G., Koopman, W. J., and Willems, P. H.
(2015) Complex I and complex III inhibition specifically increase cytosolic hydrogen
peroxide levels without inducing oxidative stress in HEK293 cells. Redox biology 6,
607-616
105. Sang, J., Yang, K., Sun, Y., Han, Y., Cang, H., Chen, Y., Shi, G., Wang, K., Zhou, J., Wang,
X., and Yi, J. (2011) SUMO2 and SUMO3 transcription is differentially regulated by
oxidative stress in an Sp1-dependent manner. The Biochemical journal 435, 489-498
106. Bossis, G., and Melchior, F. (2006) Regulation of SUMOylation by reversible oxidation of
SUMO conjugating enzymes. Molecular cell 21, 349-357
107. Manza, L. L., Codreanu, S. G., Stamer, S. L., Smith, D. L., Wells, K. S., Roberts, R. L., and
Liebler, D. C. (2004) Global shifts in protein sumoylation in response to electrophile and
oxidative stress. Chemical research in toxicology 17, 1706-1715
108. Rauthan, M., Ranji, P., Abukar, R., and Pilon, M. (2015) A Mutation in Caenorhabditis
elegans NDUF-7 Activates the Mitochondrial Stress Response and Prolongs Lifespan via
ROS and CED-4. 5, 1639-1648
78
109. Pirkmajer, S., and Chibalin, A. V. (2011) Serum starvation: caveat emptor. American
journal of physiology. Cell physiology 301, C272-279
110. Hailey, D. W., Rambold, A. S., Satpute-Krishnan, P., Mitra, K., Sougrat, R., Kim, P. K.,
and Lippincott-Schwartz, J. (2010) Mitochondria supply membranes for autophagosome
biogenesis during starvation. Cell 141, 656-667
111. Gomes, L. C., Di Benedetto, G., and Scorrano, L. (2011) During autophagy mitochondria
elongate, are spared from degradation and sustain cell viability. Nature cell biology 13,
589-598
112. Rambold, A. S., Kostelecky, B., Elia, N., and Lippincott-Schwartz, J. (2011) Tubular
network formation protects mitochondria from autophagosomal degradation during nutrient
starvation. Proceedings of the National Academy of Sciences 108, 10190-10195
113. Yuan, Y., Hilliard, G., Ferguson, T., and Millhorn, D. E. (2003) Cobalt inhibits the
interaction between hypoxia-inducible factor-α and von Hippel-Lindau protein by direct
binding to hypoxia-inducible factor-α. Journal of Biological Chemistry 278, 15911-15916
114. Chavez, A., Miranda, L. F., Pichiule, P., and Chavez, J. C. (2008) Mitochondria and
hypoxia-induced gene expression mediated by hypoxia-inducible factors. Annals of the New
York Academy of Sciences 1147, 312-320
115. Chandel, N. S., Maltepe, E., Goldwasser, E., Mathieu, C. E., Simon, M. C., and Schumacker,
P. T. (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription.
Proceedings of the National Academy of Sciences 95, 11715-11720
116. Chang, C. C., Naik, M. T., Huang, Y. S., Jeng, J. C., Liao, P. H., Kuo, H. Y., Ho, C. C.,
Hsieh, Y. L., Lin, C. H., Huang, N. J., Naik, N. M., Kung, C. C., Lin, S. Y., Chen, R. H.,
Chang, K. S., Huang, T. H., and Shih, H. M. (2011) Structural and functional roles of Daxx
SIM phosphorylation in SUMO paralog-selective binding and apoptosis modulation.
Molecular cell 42, 62-74
117. Tan, J.-A. T., Song, J., Chen, Y., and Durrin, L. K. (2010) Phosphorylation-dependent
interaction of SATB1 and PIAS1 directs SUMO-regulated caspase cleavage of SATB1.
Molecular and cellular biology 30, 2823-2836
118. Wu, H., Sun, L., Zhang, Y., Chen, Y., Shi, B., Li, R., Wang, Y., Liang, J., Fan, D., and Wu,
G. (2006) Coordinated regulation of AIB1 transcriptional activity by sumoylation and
phosphorylation. Journal of Biological Chemistry 281, 21848-21856
119. Zhang, J., Yuan, C., Wu, J., Elsayed, Z., and Fu, Z. (2015) Polo-like kinase 1-mediated
phosphorylation of Forkhead box protein M1b antagonizes its SUMOylation and facilitates
its mitotic function. The Journal of biological chemistry 290, 3708-3719
120. Zunino, R., Schauss, A., Rippstein, P., Andrade-Navarro, M., and McBride, H. M. (2007)
The SUMO protease SENP5 is required to maintain mitochondrial morphology and
function. Journal of cell science 120, 1178-1188
121. Guo, C., Hildick, K. L., Luo, J., Dearden, L., Wilkinson, K. A., and Henley, J. M. (2013)
SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death
79
following ischaemia. The EMBO journal 32, 1514-1528
122. Huang, C., Han, Y., Wang, Y., Sun, X., Yan, S., Yeh, E. T. H., Chen, Y., Cang, H., Li, H.,
and Shi, G. (2009) SENP3 is responsible for HIF􀋭1 transactivation under mild oxidative
stress via p300 de􀋭SUMOylation. The EMBO journal 28, 2748-2762
123. Krumova, P., and Weishaupt, J. H. (2013) Sumoylation in neurodegenerative diseases.
Cellular and molecular life sciences : CMLS 70, 2123-2138
124. Bettermann, K., Benesch, M., Weis, S., and Haybaeck, J. (2012) SUMOylation in
carcinogenesis. Cancer letters 316, 113-125
125. Huang, C. J., Wu, D., Khan, F. A., and Huo, L. J. (2015) DeSUMOylation: An Important
Therapeutic Target and Protein Regulatory Event. DNA and cell biology 34, 652-660
126. Fulda, S., Galluzzi, L., and Kroemer, G. (2010) Targeting mitochondria for cancer therapy.
Nature reviews Drug discovery 9, 447-464
127. Guo, W.-h., Yuan, L.-h., Xiao, Z.-h., Liu, D., and Zhang, J.-x. (2011) Overexpression of
SUMO-1 in hepatocellular carcinoma: a latent target for diagnosis and therapy of hepatoma.
Journal of cancer research and clinical oncology 137, 533-541
128. Gogvadze, V., Orrenius, S., and Zhivotovsky, B. (2008) Mitochondria in cancer cells: what
is so special about them? Trends in cell biology 18, 165-173