Accumulation mechanism of mutant mitochondrial DNA in C. elegans

• Project/Area Number: 15K19029
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Jichi Medical University
• Principal Investigator: Kasashima Katsumi 自治医科大学, 医学部, 講師 (80382844)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ミトコンドリアDNA / 欠失型mtDNAの蓄積 / 線虫 / TFAM / 欠失型ミトコンドリアDNA / mtDNA分配 / ミトコンドリアDNA (mtDNA) / 欠失型mtDNA蓄積

Outline of Final Research Achievements

Accumulation of mitochondrial DNA (mtDNA) containing mutation or deletion will be a cause of mitochondrial disease, however, the molecular mechanism and regulating factors in organisms are largely unknown. In this study, we used C. elegans strain LB138 that contains wild-type and deleted mtDNA molecules in heteroplasmic as a model, to identify the regulatory factors in the process. We knocked down several genes that are involved in mtDNA maintenance in LB138. As a result, we found that knockdown of HMG-5, a homologue of human TFAM, significantly reduced the rate of content of deleted mtDNA per wild-type. We then reduced the amount of mtDNA copy number in LB138 by using a replication inhibitor, and examined the effect. The reduction of mtDNA copy number did not significantly affect the mutant rate, suggesting that HMG-5 is involved in stable maintenance of deleted mtDNA molecule independently of the mtDNA copy number maintenance.

Research Products

• [Journal Article] Characterization of Bombyx mori mitochondrial transcription factor A, a conserved regulator of mitochondrial DNA (2017)
  • Author(s): Sumitani Megumi、Kondo Mari、Kasashima Katsumi、Endo Hitoshi、Nakamura Kaoru、Misawa Toshihiko、Tanaka Hiromitsu、Sezutsu Hideki
  • Journal Title: Gene Volume: 608 Pages: 103-113
  • DOI: 10.1016/j.gene.2016.12.021
  • Peer Reviewed
• [Journal Article] Developmentally-regulated RNA-binding Protein 1 (Drb1)/RNA-binding Motif Protein 45 (RBM45), a Nuclear-cytoplasmic Trafficking Protein, Forms TAR DNA-binding Protein 43 (TDP-43)-mediated Cytoplasmic Aggregates (2016)
  • Author(s): 5.Mashiko T, Sakashita E, Kasashima K, Tominaga K, Kuroiwa K, NozakiY, Matsuura T, Hamamoto T, Endo H
  • Journal Title: J Biol Chem Volume: 291 Issue: 29 Pages: 14996-15007
  • DOI: 10.1074/jbc.m115.712232
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of Malaria Infection in Transgenic Anopheline Mosquitoes Lacking Salivary Gland Cells. (2016)
  • Author(s): Yamamoto DS, Sumitani M, Kasashima K, Sezutsu H, Matsuoka H.
  • Journal Title: PLoS Pathog. Volume: 12 Issue: 9 Pages: e1005872-e1005872
  • DOI: 10.1371/journal.ppat.1005872
  • Peer Reviewed / Open Access
• [Journal Article] Interaction of human mitochondrial transcription factor A in mitochondria: its involvement in the dynamics of mitochondrial DNA nucleoids. (2015)
  • Author(s): Katsumi Kasashima and Hitoshi Endo
  • Journal Title: Genes to Cells Volume: 20 Issue: 12 Pages: 1017-1027
  • DOI: 10.1111/gtc.12306
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Establishment of a specific cell death induction system in Bombyx mori by a transgene with the conserved apoptotic regulator, mouse Bcl-2-associated X protein (mouse Bax). (2015)
  • Author(s): M. Sumitani, T. Sakurai, Katsumi Kasashima, S. Kobayashi, K. Uchino, R. Kanzaki, T. Tamura, and H. Sezutsu
  • Journal Title: Insect Molecular Biology Volume: 24 Issue: 6 Pages: 671-680
  • DOI: 10.1111/imb.12192
  • Peer Reviewed
• [Presentation] 保存されたTFAMのdimer化とその様式および細胞内の役割について (2017)
  • Author(s): 笠嶋克巳、炭谷めぐみ、遠藤仁司
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Property of C. elegans HMG-5, a homologue of TFAM, and its implication into mtDNA maintenance. (2016)
  • Author(s): Katsumi Kasashima, Megumi Sumitani, Hitoshi Endo
  • Organizer: The 13th Conference of Asian Society for Mitochondrial Research and Medicine
  • Place of Presentation: TKP Garden City Shinagawa (Tokyo, Shinagawa)
  • Year and Date: 2016-10-30
  • Int'l Joint Research
• [Presentation] TFAMによるミトコンドリアDNA動態調節機構の解析 (2015)
  • Author(s): 笠嶋克巳、遠藤仁司
  • 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との合同大会）
  • Place of Presentation: 神戸国際展示場（兵庫県神戸市）
  • Year and Date: 2015-12-01