Cationic oligopeptide-conjugated mitochondria targeting sequence as a novel carrier system for mitochondria

Gwang Sig Yu; Jin Han; Kyung Soo Ko; Joon Sig Choi

Macromolecular Research, Vol.22, No.1, 42-46, January, 2014

DOI10.1007/s13233-014-2003-3 Export Citation

Cationic oligopeptide-conjugated mitochondria targeting sequence as a novel carrier system for mitochondria

Gwang Sig Yu, Jin Han¹, Kyung Soo Ko^{2, †}, and Joon Sig Choi^†

Department of Biochemistry, College of Natural Science, Chungnam National University, Daejeon, 305-764, Korea
¹Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, 614-735, Korea
²Department of Internal Medicine, Sanggye Paik Hospital, Cardiovascular and Metabolic Disease Center, Inje University, Seoul, 139-707, Korea

E-mail:,

Mitochondria are crucial subcellular organelles for cell death and energy production. Mitochondrial dysfunction contributes to many human diseases. Gaining access to this organelle would create a powerful means for treating various diseases, including cancer. However, delivering bioactive materials to the mitochondria is hampered by the presence of the plasma membrane and mitochondrial membrane. To overcome this problem, we introduced a short cationic oligopeptide composed of histidines and arginines (H3R9) to the mitochondria-targeting sequence (MTS). Synthesized MTS-H3R9 was efficiently trans-localized to the mitochondria in HeLa cells according to confocal microscopy and flow cytometry studies. By combining these two distinct characteristics, cell-penetrating and mitochondria-targeting, MTS-H3R9 displayed much facilitated intracellular uptake and localization to the mitochondria. Such mitochondria-targeting peptides conjugated with functional peptides will enable effective translocalization of bioactive materials to the mitochondria.

Keywords:mitochondria targeting sequence;peptide;drug delivery;amino acids

[References]

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Schapira AHV, Mann VM, Cooper JM, Krige D, Jenner PJ, Marsden CD, Ann. Neurol., 32, S116 (1992)
Duchen MR, Diabetes, 53, S96 (2004)
Modica-Napolitano JS, Singh KK, Mitochondrion, 4, 755 (2004)
Raha S, Robinson BH, Trends Biochem. Sci., 25, 502 (2000)
Torchilin VP, Annu. Rev. Biomed. Eng., 8, 343 (2006)
Chen LB, Annu. Rev. Cell Biol., 4, 155 (1988)
Boddapati SV, Tongcharoensirikul P, Hanson RN, D’Souza GG, Torchilin VP, Weissig V, J. Liposome Res., 15, 49 (2005)
Cheng G, Lopez M, Zielonka J, Hauser AD, Joseph J, McAllister D, Rowe JJ, Sugg SL, Williams CL, Kalyanaraman B, Cancer Biol. Ther., 12, 707 (2011)
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Barrell BG, Bankier AT, Drouin J, Nature, 282, 189 (1979)
Sewards R, Wiseman B, Jacobs HT, Mol. Gen. Genet., 245, 760 (1994)
Yu GS, Bae YM, Choi H, Kong B, Choi IS, Choi JS, Bioconjugate Chem., 22, 1046 (2011)
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Maarse AC, Van Loon AP, Riezman H, Gregor I, Schatz G, Grivell LA, Embo J., 3, 2831 (1984)
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Yu GS, Bae YM, Kim JY, Han J, Ko KS, Choi JS, Macromol. Res., 20(11), 1156 (2012)
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Claros MG, Vincens P, Eur. J. Biochem., 241, 779 (1996)
Maarse AC, Van Loon AP, Riezman H, Gregor I, Schatz G, Grivell LA, Embo J., 3, 2831 (1984)
Rothbard JB, Jessop TC, Lewis RS, Murray BA, Wender PA, J. Am. Chem. Soc., 126(31), 9506 (2004)
Behr JP, Chimia, 51, 34 (1997)
Yu GS, Bae YM, Kim JY, Han J, Ko KS, Choi JS, Macromol. Res., 20(11), 1156 (2012)
Hansel A, Kuschel L, Hehl S, Lemke C, Agricola HJ, Hoshi T, Heinemann SH, Faseb J., 16, 911 (2002)
Claros MG, Vincens P, Eur. J. Biochem., 241, 779 (1996)

[Referenced By]

[1] Mecocci P, Macgarvey U, Beal MF, Ann. Neurol., 36, 747 (1994)

[2] Tabrizi SJ, Workman J, Hart PE, Mangiarini L, Mahal A, Bates G, Cooper JM, Schapira AHV, Ann. Neurol., 47, 80 (2000)

[3] Schapira AHV, Mann VM, Cooper JM, Krige D, Jenner PJ, Marsden CD, Ann. Neurol., 32, S116 (1992)

[4] Duchen MR, Diabetes, 53, S96 (2004)

[5] Modica-Napolitano JS, Singh KK, Mitochondrion, 4, 755 (2004)

[6] Raha S, Robinson BH, Trends Biochem. Sci., 25, 502 (2000)

[7] Torchilin VP, Annu. Rev. Biomed. Eng., 8, 343 (2006)

[8] Chen LB, Annu. Rev. Cell Biol., 4, 155 (1988)

[9] Boddapati SV, Tongcharoensirikul P, Hanson RN, D’Souza GG, Torchilin VP, Weissig V, J. Liposome Res., 15, 49 (2005)

[10] Cheng G, Lopez M, Zielonka J, Hauser AD, Joseph J, McAllister D, Rowe JJ, Sugg SL, Williams CL, Kalyanaraman B, Cancer Biol. Ther., 12, 707 (2011)

[11] Jiang J, Stoyanovsky DA, Belikova NA, Tyurina YY, Zhao Q, Tungekar MA, Kapralova V, Huang Z, Mintz AH, Greenberger JS, Kagan VE, Radiat. Res., 172, 706 (2009)

[12] Rodriguez-Enriquez S, Hernandez-Esquivel L, Marin-Hernandez A, Dong LF, Akporiaye ET, Neuzil J, Ralph SJ, Moreno-Sanchez R, Biochim. Biophys. Acta, 1817, 1597 (2012)

[13] Biswas S, Dodwadkar NS, Piroyan A, Torchilin VP, Biomaterials, 33, 4773 (2012)

[14] Muratovska A, Lightowlers RN, Taylor RW, Turnbull DM, Smith RA, Wilce JA, Martin SW, Murphy MP, Nucleic Acids Res., 29, 1852 (2001)

[15] Weissig V, D’Souza GG, Torchilin VP, J. Control. Release, 75, 401 (2001)

[16] Lyrawati D, Trounson A, Cram D, Pharm. Res., 28, 2848 (2011)

[17] Weissig V, Crit. Rev. Ther. Drug Carrier Syst., 20, 1 (2003)

[18] Yousif LF, Stewart KM, Horton KL, Kelley SO, Chembiochem, 10, 2081 (2009)

[19] Lee M, Choi JS, Choi MJ, Pak YK, Rhee BD, Ko KS, J. Drug Target., 15, 115 (2007)

[20] Li L, Geisler I, Chmielewski J, Cheng JX, J. Control. Release, 142, 259 (2010)

[21] Burns RJ, Murphy MP, Arch. Biochem. Biophys., 339, 33 (1997)

[22] Fernandex-Carneado J, Van Gool M, Martos V, Castel S, Prados P, de Mendoza J, Giralt E, J. Am. Chem. Soc., 127(3), 869 (2005)

[23] Horobin RW, Trapp S, Weissig V, J. Control. Release, 121, 125 (2007)

[24] Roise D, Theiler F, Horvath SJ, Tomich JM, Richards JH, Allison DS, Schatz G, Embo J., 7, 649 (1988)

[25] Barrell BG, Bankier AT, Drouin J, Nature, 282, 189 (1979)

[26] Sewards R, Wiseman B, Jacobs HT, Mol. Gen. Genet., 245, 760 (1994)

[27] Yu GS, Bae YM, Choi H, Kong B, Choi IS, Choi JS, Bioconjugate Chem., 22, 1046 (2011)

[28] Schmidt N, Mishra A, Lai GH, Wong GC, Febs Lett., 584, 1806 (2010)

[29] Maarse AC, Van Loon AP, Riezman H, Gregor I, Schatz G, Grivell LA, Embo J., 3, 2831 (1984)

[30] Rothbard JB, Jessop TC, Lewis RS, Murray BA, Wender PA, J. Am. Chem. Soc., 126(31), 9506 (2004)

[31] Behr JP, Chimia, 51, 34 (1997)

[32] Yu GS, Bae YM, Kim JY, Han J, Ko KS, Choi JS, Macromol. Res., 20(11), 1156 (2012)

[33] Hansel A, Kuschel L, Hehl S, Lemke C, Agricola HJ, Hoshi T, Heinemann SH, Faseb J., 16, 911 (2002)

[34] Claros MG, Vincens P, Eur. J. Biochem., 241, 779 (1996)

[35] Maarse AC, Van Loon AP, Riezman H, Gregor I, Schatz G, Grivell LA, Embo J., 3, 2831 (1984)

[36] Rothbard JB, Jessop TC, Lewis RS, Murray BA, Wender PA, J. Am. Chem. Soc., 126(31), 9506 (2004)

[37] Behr JP, Chimia, 51, 34 (1997)

[38] Yu GS, Bae YM, Kim JY, Han J, Ko KS, Choi JS, Macromol. Res., 20(11), 1156 (2012)

[39] Hansel A, Kuschel L, Hehl S, Lemke C, Agricola HJ, Hoshi T, Heinemann SH, Faseb J., 16, 911 (2002)

[40] Claros MG, Vincens P, Eur. J. Biochem., 241, 779 (1996)