Analysis of the relationship between the loss of ER-mitochondria interaction and mitochondrial diseases

• Project/Area Number: 26870545
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics; Cell biology
• Research Institution: Saitama Medical University
• Principal Investigator: Kishita Yoshihito 埼玉医科大学, 医学部, 研究員 (20634398)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ミトコンドリア / 小胞体 / ミトコンドリア病 / 遺伝性疾患 / MAM

Outline of Final Research Achievements

Mitochondria are essential for energy production through oxidative phosphorylation and are dynamic organelles that continuously undergo fusion and fission. Mutations in mitochondrial or nuclear genes cause mitochondrial dysfunction in various organs and energy generation disorders. To identify novel causative genes for mitochondrial disorders, we performed whole exome sequencing on affected subjects. I identified compound heterozygous variants in OCIAD2 gene whose product localizes at mitochondria and mitochondria-associated ER membrane (MAM). In the present study, I found apparent loss of protein probably due to the instability of mutant gene products. The elongated and tubular mitochondria were increased in the patient derived fibroblasts. siRNA-mediated knockdown of OCIAD2 also leads to mitochondrial interconnectivity and elongation. These findings indicate that mutations in OCIAD2 cause mitochondrial disorder and defects in mitochondrial fission/fusion.

Research Products

• [Journal Article] A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain deficiency. (2016)
  • Author(s): Kohda M, Mizuno Y, Hirata T, Yatsuka Y, Yamashita, Okuda A, Borna NN, Banshoya K, Ohnuma K, Suzuki T, Nagao A, Maehata H, Matsuda F, Higasa K, Nagasaki M, Yasuda J, Yamamoto M, Fushimi T, Shimura M, Kaiho-Ichimoto K, Harashima H, Yamazaki T, Mori M, Murayama K, Ohtake A, Okazaki Y.
  • Journal Title: PLoS Genetics: Volume: 12(1) Issue: 1 Pages: e1005679-e1005679
  • DOI: 10.1371/journal.pgen.1005679
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. (2015)
  • Author(s): Kishita Y, Pajak A, Bolar NA, Marobbio CM, et al
  • Journal Title: Am J Hum Genet. Volume: 97(5) Issue: 5 Pages: 761-8
  • DOI: 10.1016/j.ajhg.2015.09.013
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Mutations in a novel mitochondria-related gene impaired mitochondrial fission/fusion balance and caused mitochondrial cytopathy (2015)
  • Author(s): 木下善仁, 鈴木聡美, 徳澤佳美, 入月浩美, 神田将和, 村山圭, 大竹明 , 岡崎康司
  • Organizer: 第15回年会日本ミトコンドリア学会
  • Place of Presentation: 福井県国際交流会館（福井県福井市）
  • Year and Date: 2015-11-19
• [Presentation] ミトコンドリアの分裂・融合の異常とミトコンドリア細胞症を引き起こす新規ミトコンドリア関連遺伝子の変異の同定と解析 (2015)
  • Author(s): 木下善仁, 鈴木聡美, 徳澤佳美, 入月浩美, 神田将和, 村山圭, 大竹明 , 岡崎康司
  • Organizer: 第13回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉医科大学創立３０周年記念講堂（埼玉県日高市）
  • Year and Date: 2015-10-30
• [Presentation] ミトコンドリア呼吸鎖異常症の原因遺伝子の包括的大規模解析 (2014)
  • Author(s): 木下善仁,徳澤佳美, 神田将和,森山陽介, 水野洋介,菅原-山下泉, 田丸俊輔 栃木秀乃,上原奈津美, 仲地豊,八塚由紀子,入月浩美,鈴木聡美,Nurun Nahar Borna, 平田智子, 的場奈々,加藤英政, 奥田晶彦, 森雅人, 安嶋まさみ, 原嶋宏子, 山崎太郎, 村山圭,大竹明, 岡﨑康司
  • Organizer: 第３７回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2014-11-25 – 2014-11-27