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.
Highlights
Mitochondrial function is essential for the development and differentiation of the two types of adipose tissue in mammals, brown adipose tissue (BAT) and white adipose tissue (WAT)
The total lipid content in WAT and BAT was significantly lower in thymidine kinase 2 (Tk2)-/- mice than in Tk2+/+ mice, and accounted for most of the decrease in tissue weight in Tk2-/- mice
Clumps of densely packed mitochondria were evident in the brown adipocytes of Tk2-/- mice (Fig. 2A, bottom) and quantitative measurements revealed that mitochondria occupied a greater proportion of the cytoplasmatic volume (Fig. 2B, bottom)
Summary
Mitochondrial function is essential for the development and differentiation of the two types of adipose tissue in mammals, brown adipose tissue (BAT) and white adipose tissue (WAT). It has long been recognized that mitochondrial activity is a major component of the differentiated phenotype of BAT, as it provides the oxidative activity required for the thermogenic function of this type of adipose tissue. The mitochondrial DNA (mtDNA) encodes 13 subunits of OXPHOS complexes I, III, IV and V that are essential for the enzymatic function of the OXPHOS system. Coordinate expression of the OXPHOS proteins encoded by the nuclear DNA (nDNA) and mtDNA genes is required for functional mitochondrial oxidative activity [5,6]
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