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Mice lacking TR4 nuclear receptor develop mitochondrial myopathy with deficiency in complex I.


ABSTRACT: The estimated incidence of mitochondrial diseases in humans is approximately 1:5000 to 1:10,000, whereas the molecular mechanisms for more than 50% of human mitochondrial disease cases still remain unclear. Here we report that mice lacking testicular nuclear receptor 4 (TR4(-/-)) suffered mitochondrial myopathy, and histological examination of TR4(-/-) soleus muscle revealed abnormal mitochondrial accumulation. In addition, increased serum lactate levels, decreased mitochondrial ATP production, and decreased electron transport chain complex I activity were found in TR4(-/-) mice. Restoration of TR4 into TR4(-/-) myoblasts rescued mitochondrial ATP generation capacity and complex I activity. Further real-time PCR quantification and promoter studies found TR4 could modulate complex I activity via transcriptionally regulating the complex I assembly factor NDUFAF1, and restoration of NDUFAF1 level in TR4(-/-) myoblasts increased mitochondrial ATP generation capacity and complex I activity. Together, these results suggest that TR4 plays vital roles in mitochondrial function, which may help us to better understand the pathogenesis of mitochondrial myopathy, and targeting TR4 via its ligands/activators may allow us to develop better therapeutic approaches.

SUBMITTER: Liu S 

PROVIDER: S-EPMC3146253 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Mice lacking TR4 nuclear receptor develop mitochondrial myopathy with deficiency in complex I.

Liu Su S   Lee Yi-Fen YF   Chou Samuel S   Uno Hideo H   Li Gonghui G   Brookes Paul P   Massett Michael P MP   Wu Qiao Q   Chen Lu-Min LM   Chang Chawnshang C  

Molecular endocrinology (Baltimore, Md.) 20110526 8


The estimated incidence of mitochondrial diseases in humans is approximately 1:5000 to 1:10,000, whereas the molecular mechanisms for more than 50% of human mitochondrial disease cases still remain unclear. Here we report that mice lacking testicular nuclear receptor 4 (TR4(-/-)) suffered mitochondrial myopathy, and histological examination of TR4(-/-) soleus muscle revealed abnormal mitochondrial accumulation. In addition, increased serum lactate levels, decreased mitochondrial ATP production,  ...[more]

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