Biomarkers in blood for mitochondrial abnormality

• Project/Area Number: 25253041
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kyushu University
• Principal Investigator: Kang Dongchon 九州大学, 医学(系)研究科(研究院), 教授 (80214716)
• Co-Investigator(Renkei-kenkyūsha): UCHIUMI TAKESHI 九州大学, 大学院医学研究院, 准教授 (80253798) ; MATSUSHIMA YUICI 九州大学, 大学院医学研究院, 助教 (20571342) ; YASUKAWA TAKEHIRO 九州大学, 大学院医学研究院, 助教 (90646720) ; SHINYA TAKAZAKI 九州大学, 大学院医学研究院, 助教 (90435149)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥46,280,000 (Direct Cost: ¥35,600,000、Indirect Cost: ¥10,680,000); Fiscal Year 2015: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000); Fiscal Year 2014: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000); Fiscal Year 2013: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
• Keywords: ミトコンドリア病 / メタボローム / プロテオーム / ミトコンドリアDNA / 臨床検査 / マイトファジー / ミトコンドリアプロテアーゼ / ミトコンドリア / ミトコンドリアゲノム / TFAM発現マウス / ｐ32ノックアウトマウス

Outline of Final Research Achievements

(1)Basic research for mitochondria: We show that 7SDNA is involved in asymmetric mode of mitochondrial DNA replication, mitochondrial protease ClPXP regulates mitochondrial mRNA through LRPPRC1 degradation, and new pathways for mitophagy regulation.
(2) Analysis of mitochondrial diseases: The metabolome and proteome analysis systems with LC/MS have been set up. Then, we performed metabolome analysis of plasma of 20 patients with mitochondrial disease, MELAS. We identified several metabolites as new candidate biomarkers for MELAS. These metabolites were also found in a mouse mitochondrial disease model. A new gene causing mitochondrial disease of a human patient is identified through an extensive genomic DNA survey by next generation DNA sequencing.

Research Products

• [Journal Article] Suppression of mitochondrial transcription initiation complexes changes the balance of replication intermediates of mitochondrial DNA and reduces 7S DNA in cultured human cells (2016)
  • Author(s): Jianhua Qu, Takehiro Yasukawa, Dongchon Kang
  • Journal Title: The Journal of Biochemistry Volume: N/A Issue: 1 Pages: 49-57
  • DOI: 10.1093/jb/mvw010
  • NAID: 40020880721
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism (2016)
  • Author(s): Ichiyama, M. Ohga, S. Ochiai, M. Tanaka, K. Matsunaga, Y. Kusuda, T. Inoue, H. Ishimura, M. Takimoto, T. Koga, Y. Hotta, T. Kang, D. Hara, T.
  • Journal Title: Pediatr Res Volume: 79 Issue: 1 Pages: 81-89
  • DOI: 10.1038/pr.2015.180
  • Peer Reviewed
• [Journal Article] Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency. (2016)
  • Author(s): Ichiyama M, Ohga S, Ochiai M, Fukushima K, Ishimura M, Torio M, Urata M, Hotta T, Kang D, Hara T.
  • Journal Title: Brain and development Volume: 38(2) Issue: 2 Pages: 253-256
  • DOI: 10.1016/j.braindev.2015.07.004
  • Peer Reviewed / Open Access
• [Journal Article] Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration. (2015)
  • Author(s): Wang L, Ishihara T, Ibayashi Y, Tatsushima K, Setoyama D, Hanada Y, Takeichi Y, Sakamoto S, Yokota S, Mihara K, Kang D, Ishihara N, Takayanagi R, Nomura M
  • Journal Title: Diabetologia Volume: 58 Issue: 10 Pages: 2371-2380
  • DOI: 10.1007/s00125-015-3704-7
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Association of hemoglobin A1c and glycated albumin with carotid atherosclerosis in community-dwelling Japanese subjects: the Hisayama Study (2015)
  • Author(s): Mukai N, Ninomiya T, Hata J, Hirakawa Y, Ikeda F, Fukuhara M, Hotta T, Koga M, Nakamura U, Kang D, Kitazono T, Kiyohara Y
  • Journal Title: Cardiovasc Diabetol Volume: 14 Issue: 1 Pages: 84-84
  • DOI: 10.1186/s12933-015-0247-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparison of two types of matrix-assisted laser desorption/ionization time-of-flight mass spectrometer for the identification and typing of Clostridium difficile (2015)
  • Author(s): Kiyosuke, M., Kibe, Y., Oho, M., Kusaba, K., Shimono, N., Hotta, T., Kang, D., Shoubuike, T., Miyamoto, H.
  • Journal Title: J Med Microbio Volume: 64 Issue: 10 Pages: 1144-1150
  • DOI: 10.1099/jmm.0.000136
  • Peer Reviewed
• [Journal Article] Overexpression of TFAM or Twinkle Increases mtDNA Copy Number and Facilitates Cardioprotection Associated with Limited Mitochondrial Oxidative Stress. (2015)
  • Author(s): Ikeda M, Ide T, Fujino T, Arai S, Saku K, Kakino T, Tyynismaa H, Yamasaki T,Yamada K, Kang D, Suomalainen A, Sunagawa K.
  • Journal Title: PLoS One. Volume: 10 Issue: 3 Pages: e0119687-e0119687
  • DOI: 10.1371/journal.pone.0119687
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of the short-term stability of specimens for clinical laboratory testing. (2015)
  • Author(s): Ikeda K, Ichikawa K, Hashiguchi T, Hidaka Y, Kang D, Maekawa M, Matsumoto H, Matsushita K, Okubo S, Tsuchiya T, Furuta K
  • Journal Title: Biopreserv Biobank Volume: 13(2) Issue: 2 Pages: 135-143
  • DOI: 10.1089/bio.2014.0072
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Collaborative derivation of reference intervals for major clinical laboratory tests in Japan (2015)
  • Author(s): Ichihara, K., Yomamoto, Y., Hotta, T., Hosogaya, S., Miyachi, H., Itoh, Y., Ishibashi, M., Kang, D
  • Journal Title: Ann Clin Biochem Volume: 13 Issue: 3 Pages: 135-143
  • DOI: 10.1177/0004563215608875
  • Peer Reviewed
• [Journal Article] Mitophagy is primarily due to alternative autophagy and requires MAPK1 and MAPK14 signaling pathway. (2015)
  • Author(s): Hirota, Y.,Yamashita, S., Kurihara, Y., Jin, X., Aihara, M., Saigusa, T., Kang, D., and Kanki, T.
  • Journal Title: Autophagy Volume: 11 Issue: 2 Pages: 332-43
  • DOI: 10.1080/15548627.2015.1023047
  • Peer Reviewed / Open Access
• [Journal Article] Crystal structure of the anion exchanger domain of human erythrocyte band 3 (2015)
  • Author(s): Arakawa T, Kobayashi-Yurugi T, Alguel Y, Iwanari H, Hatae H, Iwata M, Abe Y, Hino T, Ikeda-Suno C, Kuma H, Kang D, Murata T, Hamakubo T, Cameron AD, Kobayashi T, Hamasaki N, Iwata S
  • Journal Title: Science Volume: 350 Issue: 6261 Pages: 680-684
  • DOI: 10.1126/science.aaa4335
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome (2015)
  • Author(s): Sakai C, Yamaguchi S, Sasaki M, Miyamoto Y, Matsushima Y, Goto YI
  • Journal Title: Human Mutation Volume: 36 Issue: 2 Pages: 232-239
  • DOI: 10.1002/humu.22730
  • Peer Reviewed
• [Journal Article] Improvement and evaluation of a 1,2-dioleoylglycerol method for measuring pancreatic lipase catalytic activity in serum, (2014)
  • Author(s): Iizuka, Y., Yamashita, K., Sakasegawa, S., Hanada, T., Tani, W., Adachi, H., Haga, R., Yamaguchi, M., Kurotani, W., Sekiguchi, M., Osawa, S., Hosogaya, S., Kang, D., Ueda, S.
  • Journal Title: Clin. Chem. Lab. Med Volume: 52 Pages: 171-173
  • Peer Reviewed / Open Access
• [Journal Article] PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells (2014)
  • Author(s): Itsumi, M., Shiota, M., Yokomizo, A., Takeuchi, A., Kashiwagi, E., Dejima, T., Inokuchi, J., Tatsugami, K., Uchiumi, T.Naito, S.
  • Journal Title: J. Mol. Endocrinol. Volume: 53 Issue: 1 Pages: 31-41
  • DOI: 10.1530/jme-13-0303
  • Peer Reviewed / Open Access
• [Journal Article] EP2 signaling mediates suppressive effects of celecoxib on androgen receptor expression and cell proliferation in prostate cancer (2014)
  • Author(s): Kashiwagi E, Shiota M, *Yokomizo A, Inokuchi J, Uchiumi T, Naito S.
  • Journal Title: Prostate Cancer P D Volume: 17 Issue: 1 Pages: 10-17
  • DOI: 10.1038/pcan.2013.53
  • Peer Reviewed / Open Access
• [Journal Article] Targeting ribosomal S6 kinases/Y-box binding protein-1 signaling improves cellular sensitivity to taxane in prostate cancer (2014)
  • Author(s): Shiota, M., Itsumi, M., Yokomizo, A., Takeuchi, A., Imada, K., Kashiwagi, E., Inokuchi, J., Tatsugami, K., Uchiumi, T., Naito, S.
  • Journal Title: The Prostate Volume: 74 Issue: 8 Pages: 829-838
  • DOI: 10.1002/pros.22799
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of protein kinase C/Twist1 signaling augments anticancer effects of androgen deprivation and enzalutamide in prostate cancer (2014)
  • Author(s): Shiota M, Yokomizo A, Takeuchi A, Imada K, Kashiwagi E, Song Y, Inokuchi J, Tatsugami K, Uchiumi T, Naito S
  • Journal Title: Clinical Cancer Research Volume: 20巻 Issue: 4 Pages: 951-961
  • DOI: 10.1158/1078-0432.ccr-13-1809
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of RSK/YB-1 signaling enhances the anti-cancer effect of enzalutamide in prostate cancer, (2014)
  • Author(s): Shiota, M., Yokomizo, A., Takeuchi, A., Itsumi, M., Imada, K., Kashiwagi, E., Inokuchi, J., Tatsugami, K., Uchiumi, T., Naito, S.
  • Journal Title: The Prostate Volume: 74 Issue: 9 Pages: 959-969
  • DOI: 10.1002/pros.22813
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Twist1 and Y-box-binding protein-1 are potential prognostic factors in bladder cancer, Urol. (2014)
  • Author(s): Song, Y. H., Shiota, M., Yokomizo, A., Uchiumi, T., Kiyoshima, K., Kuroiwa, K., Oda, Y., Naito, S.
  • Journal Title: Oncol. Volume: 32 Pages: 31-37
  • Peer Reviewed / Open Access
• [Journal Article] Tor and the Sin3-Rpd3 complex regulate expression of the mitophagy receptor protein Atg32 in yeast. (2014)
  • Author(s): Aihara M, Jin X, Kurihara Y, Yoshida Y, Matsushima Y, Oku M, Hirota Y, Saigusa T, Aoki Y, Uchiumi T, Yamamoto T, Sakai Y, Kang D, Kanki T.
  • Journal Title: Journal of Cell Science Volume: 127 Pages: 3184-96
  • DOI: 10.1242/jcs.153254
  • Peer Reviewed / Open Access
• [Journal Article] A novel mutation in protein C gene (PROC) causing severe phenotype in neonatal period, Pediatr (2014)
  • Author(s): Unal, S., Gumruk, F., Yigit, S., Tuncer, M., Tavil, B., Cil, O., Takci, S., Urata, M., Hotta, T., Kang, D., Cetin, M.
  • Journal Title: Blood Cancer Volume: 61 Issue: 4 Pages: 763-764
  • DOI: 10.1002/pbc.24782
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Thresholds of various glycemic measures for diagnosing diabetes based on prevalence of retinopathy in community-dwelling Japanese subjects: the Hisayama Study. (2014)
  • Author(s): Mukai N, Yasuda M, Ninomiya T, Hata J, Hirakawa Y, Ikeda F, Fukuhara M, Hotta T, Koga M, Nakamura U, Kang D, Kitazono T, Kiyohara Y.
  • Journal Title: Cardiovasc Diabetol Volume: 13 Issue: 1 Pages: 45-45
  • DOI: 10.1186/1475-2840-13-45
  • Peer Reviewed / Open Access
• [Journal Article] Staphylococcal endocarditis as the first manifestation of heritable protein S deficiency in childhood, (2014)
  • Author(s): Hoshina, T., Nakashima, Y., Sato, D., Nanishi, E., Nishio, H., Nagata, H., Yamamura, K., Doi, T., Shiokawa, Y., Koga, Y., Kang, D., Ohga, S., Hara, T.
  • Journal Title: J. Infect. Chemother Volume: 20 Issue: 2 Pages: 128-130
  • DOI: 10.1016/j.jiac.2013.08.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1 (2014)
  • Author(s): Baba, T., Otake, H., Sato, T., Miyabayashi, K., Shishido, Y., Wang, C. Y., Shima, Y., Kimura, H., Yagi, M., Ishihara, Y., Hino, S., Ogawa, H., Nakao, M., Yamazaki, T., Kang, D., Ohkawa, Y., Suyama, M., Chung, B. C., Morohashi, K.
  • Journal Title: Nat. Commun. Volume: 5 Pages: 3634-3634
  • NAID: 130005085557
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Casein kinase 2 is essential for mitophagy. (2013)
  • Author(s): Kanki T., Kurihara Y., Jin X., Goda T., Ono Y., Aihara M., Hirota Y., Saigusa T., Aoki Y., Uchiumi T., Kang D.
  • Journal Title: EMBO reports Volume: 14巻 Issue: 9 Pages: 788-794
  • DOI: 10.1038/embor.2013.114
  • Peer Reviewed
• [Journal Article] Effects of overexpression of mitochondrial transcription factor A on lifespan and oxidative stress response in Drosophila melanogaster (2013)
  • Author(s): Matsuda T, Kanki T, Tanimura T, Kang D, Matsuura ET
  • Journal Title: Biochem Biophys Res Commun Volume: 430(2) Issue: 2 Pages: 717-21
  • DOI: 10.1016/j.bbrc.2012.11.084
  • Peer Reviewed
• [Journal Article] Effects of DNA lesions on the transcription reaction of mitochondrial RNA polymerase: implications for bypass RNA synthesis on oxidative DNA lesions, (2013)
  • Author(s): Nakanishi, N., Fukuoh, A., Kang, D., Iwai, S.Kuraoka, I.
  • Journal Title: Mutagenesis Volume: 28 Issue: 1 Pages: 117-123
  • DOI: 10.1093/mutage/ges060
  • Peer Reviewed
• [Journal Article] Protein C deficiency as the major cause of thrombophilias in childhood, (2013)
  • Author(s): Ohga, S., Ishiguro, A., Takahashi, Y., Shima, M., Taki, M., Kaneko, M., Fukushima, K., Kang, D.Hara, T
  • Journal Title: ediatrics international : official journal of the Japan Pediatric Society Volume: 55 Issue: 3 Pages: 267-271
  • DOI: 10.1111/ped.12102
  • Peer Reviewed
• [Journal Article] Mutation and functional analysis of ABCC2/multidrug resistance protein 2 in a Japanese patient with Dubin-Johnson syndrome (2013)
  • Author(s): Uchiumi T, Tanamachi H, Kuchiwaki K, Kajita M, Matsumoto S, Yagi M, Kanki T, Kang D
  • Journal Title: Hepatol Res Volume: 43(5) Issue: 5 Pages: 569-75
  • DOI: 10.1111/j.1872-034x.2012.01103.x
  • NAID: 10031183491
  • Peer Reviewed
• [Journal Article] Dihydroorotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction (2012)
  • Author(s): Fang, J. Uchiumi, T. Yagi, M. Matsumoto, S. Amamoto, R. Takazaki, S. Yamaza, H. Nonaka, K. Kang, D.
  • Journal Title: Bioscience reports Volume: 33 Issue: 2 Pages: 217-227
  • DOI: 10.1042/bsr20120097
  • Peer Reviewed
• [Presentation] 酸化ストレスの発生と制御 (2015)
  • Author(s): 康 東天
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Mitochondrial p32 is essential for OXPHOS and TLR-mediated activation in dendritic cells (2015)
  • Author(s): 康 東天
  • Organizer: The 12th Conference of Asian Society for Mitochondrial Research and Medicine
  • Place of Presentation: 中国、杭州
  • Year and Date: 2015-11-14
  • Int'l Joint Research / Invited
• [Presentation] TFAMとp32の機能から考えるミトコンドリアの維持と疾患 (2015)
  • Author(s): 康 東天
  • Organizer: 第68回日本酸化ストレス学会
  • Place of Presentation: 鹿児島
  • Year and Date: 2015-06-11
  • Invited
• [Presentation] ミトコンドリア異常と臨床検査 (2015)
  • Author(s): 康 東天
  • Organizer: 第29回日本医学会総会2015関西・分科会
  • Place of Presentation: 京都
  • Year and Date: 2015-04-13
  • Invited
• [Presentation] Brain－ and heart-specific disruption of p32 gene in mice causes vacuolar degenereation in mid-brain and dilated cardiomyopathy (2014)
  • Author(s): Kang, Dongchon
  • Organizer: The 9th International Symposium of Genomic Medicine
  • Place of Presentation: Changhua, Taiwan
  • Year and Date: 2014-11-15 – 2014-11-16
  • Invited
• [Presentation] Tissue specific KO mice of p32/gC1qR, a mitochondrial RNA chaperone (2014)
  • Author(s): Kang, Dongchon
  • Organizer: The 11th Conference of Asian Society for Mitochondrial Research and Medicine
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2014-11-14 – 2014-11-15
  • Invited
• [Presentation] 細胞と個体におけるミトコンドリアの形成と維持機能 (2014)
  • Author(s): 康 東天
  • Organizer: 第87回日本生化学大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] 血清脂質の基準範囲を考える (2014)
  • Author(s): 康 東天
  • Organizer: 第54回日本臨床化学会年次学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-09-05 – 2014-09-07
  • Invited
• [Presentation] ミトコンドリア生物学からミトコンドリア疾患学へ (2014)
  • Author(s): 康 東天
  • Organizer: 第87回日本内分泌学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24 – 2014-04-26
  • Invited
• [Presentation] REAL1 and p32:factors for mitochondrial ribosome assembly (2013)
  • Author(s): Kang, Dongchon
  • Organizer: The 10th Conference of the Asian Society of Mitochondrial Research and Medicine(A-mit)
  • Place of Presentation: Grand Hilton Seoul Hotel.
  • Invited
• [Presentation] 臨床検査医/検査部長の立場から望むこと：臨床検査学サイエンティストの養成 (2013)
  • Author(s): 康 東天
  • Organizer: 第60回日本臨床検査医学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Invited
• [Presentation] 項目コード（JLAC10)を用いた多施設間検査情報のための取り組みと問題点 (2013)
  • Author(s): 康 東天
  • Organizer: 第60回日本臨床検査医学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Invited
• [Remarks] 九州大学大学院医学研究院 臨床検査医学
  • URL: http://www.cclm2.med.kyushu-u.ac.jp/
• [Remarks] 九州大学病院検査部 臨床検査医学分野
  • URL: http://www.med.kyushu-u.ac.jp/cclm/
• [Remarks] 九州大学病院検査部
  • URL: http://www.med.kyushu-u.ac.jp/cclm/