Elucidation of mechanism of Leigh syndrome caused by impaired mitochondrial division using iPS cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08289
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: National Defense Medical College
• Principal Investigator: Matsumoto Hiroshi 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 小児科学, 講師 (00536229)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: iPS細胞 / DNM1L / ミトコンドリア / Leigh症候群

Outline of Final Research Achievements

Dynamin 1-like (DNM1L) is a nuclear gene encoding DRP1, which regulates intracellular mitochondrial fission. It is known that fibroblasts with heterozygous DNM1L mutation exhibit an abnormal mitochondrial and peroxisomal morphology, however, the morphology and function of mitochondria in neuronal cells have not been reported so far. We obtained iPS cells from patient with Leigh syndrome caused by heterozygous DNM1L mutation, and differentiated to neuronal cells. The differentiated neuronal cells were served for analysis of mitochondrial morphology and function by electron microscopy and oxygen consumption rate. The results exhibited that DNM1L mutant neuronal cells have abnormally elongated mitochondria and reduced oxygen consumption rate.

Free Research Field

小児科学、神経科学

Academic Significance and Societal Importance of the Research Achievements

DNM1Lはミトコンドリア分裂を制御する核遺伝子であり、その片アレル変異により種々の中枢神経障害が生じる事が報告されています。DNM1Lに変異を有する線維芽細胞では、ミトコンドリアの形態異常を呈することが知られていますが、神経細胞においてどうなるかは分かっていませんでした。私達はiPS細胞を神経細胞に分化誘導し、ミトコンドリアの形態および機能異常が神経細胞においても見られることを示しました。