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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / biosynthesis
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Aminoimidazole Carboxamide / analogs & derivatives
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Aminoimidazole Carboxamide / pharmacology
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Animals
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Cells, Cultured
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Electron Transport Complex I / deficiency*
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Electron Transport Complex I / genetics
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Electron Transport Complex I / metabolism
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Gene Expression Regulation / drug effects
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Humans
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Lactic Acid / blood
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Metformin / pharmacology
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Mice
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondria / pathology
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Mitochondria / ultrastructure
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Mitochondrial Myopathies / blood
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Mitochondrial Myopathies / complications
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Mitochondrial Myopathies / metabolism*
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Mitochondrial Myopathies / pathology
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Muscle Weakness / blood
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Muscle Weakness / complications
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Muscle Weakness / metabolism
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Muscle Weakness / pathology
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology
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Muscle, Skeletal / ultrastructure
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Myoblasts / drug effects
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Myoblasts / metabolism
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Myoblasts / pathology
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NADH Dehydrogenase / genetics
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NADH Dehydrogenase / metabolism
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Physical Conditioning, Animal
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Receptors, Steroid / deficiency*
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Receptors, Steroid / metabolism
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Receptors, Thyroid Hormone / deficiency*
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Receptors, Thyroid Hormone / metabolism
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Ribonucleotides / pharmacology
Substances
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Nr2c2 protein, mouse
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Receptors, Steroid
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Receptors, Thyroid Hormone
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Ribonucleotides
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Lactic Acid
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Aminoimidazole Carboxamide
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Adenosine Triphosphate
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Metformin
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NADH Dehydrogenase
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Electron Transport Complex I
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AICA ribonucleotide