Studies on skeletal muscle fiber-type specific responses to pathogenic mtDNA

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K14719
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cell biology
• Research Institution: University of Tsukuba
• Principal Investigator: NAKADA Kazuto 筑波大学, 生命環境系, 教授 (80323244)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: ミトコンドリア / ミトコンドリアDNA / 突然変異 / 骨格筋 / インスリンシグナル / ミトコンドリア病 / モデルマウス

Outline of Final Research Achievements

To examine mechanisms for cell-type specific sensitivities to mutant mitochondrial DNA (mtDNA), we used model mice heteroplasmic for wild-type mtDNA and pathogenic mtDNA with a deletion (del-mtDNA). In skeletal muscles with a high loads of del-mtDNA, mitochondrial respiration defects observed in slow oxidative type 1 and fast oxido-glycolytic type 2A/2X fibers, but not in fast glycolytic type 2B fibers that the relocation of glucose transporter 4 (GULT4) to sarcolemma from cytoplasm was accelerated. Chemical deconditioning of the relocation of GLUT4 induced mitochondrial respiration defects in 2B fiber and creation of ragged-red fibers in fast muscle tissues. Our findings indicated that relocation of GLUT4 in skeletal muscle fibers is necessary for tolerance to accumulation of del-mtDNA and also suggested that controls of insulin signaling via GULT4 would be a target for recovering mitochondrial respiration defects of cells with oxidative property in mtDNA-mediated disorders.

Free Research Field

細胞生物学