2026-02-19 コロンビア大学
In TK2 deficiency, movement is lost as mitochondria inside cells become dysfunctional. The left image shows normal mitochondria in an unaffected mouse; the right image shows abnormal mitochondria from a mouse with TK2 deficiency. Images from Villarroya, et al. PLoS ONE 6(12): e29691
<関連情報>
- https://www.cuimc.columbia.edu/news/how-columbia-neurologist-changing-outlook-children-devastating-muscle-disease
- https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029691
チミジンキナーゼ2欠損によるミトコンドリアDNA枯渇は、マウスの脂肪組織の異常な発達とアディポカインレベルを引き起こす Thymidine Kinase 2 Deficiency-Induced Mitochondrial DNA Depletion Causes Abnormal Development of Adipose Tissues and Adipokine Levels in Mice
Joan Villarroya ,Beatriz Dorado,Maya R. Vilà,Elena Garcia-Arumí,Pere Domingo,Marta Giralt,Michio Hirano,Francesc Villarroya
PLOS One Published:December 27, 2011
DOI:https://doi.org/10.1371/journal.pone.0029691
Abstract
Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues.
