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Published on: July 14, 2016
Mice lacking TR4 nuclear receptor develop mitochondrial myopathy with deficiency in complex I
Su Liu1, Yi-Fen Lee, Samuel Chou
1Department of Pathology, University of Rochester, Medical Center, Rochester, New York 14646, USA.
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.
Insights
Testicular nuclear receptor 4 (TR4) is crucial for mitochondrial function. TR4 deficiency causes mitochondrial myopathy by impairing electron transport chain complex I, offering therapeutic targets for mitochondrial diseases.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Mitochondrial diseases affect 1:5000-1:10,000 individuals, with unclear molecular mechanisms in over 50% of cases.
- Mitochondrial myopathies represent a significant subset of these debilitating conditions.
Purpose of the Study:
- To investigate the role of testicular nuclear receptor 4 (TR4) in mitochondrial function and myopathy.
- To elucidate the molecular mechanisms by which TR4 influences mitochondrial health.
Main Methods:
- Mice lacking TR4 (TR4(-/-)) were analyzed for mitochondrial function and muscle histology.
- Biochemical assays measured serum lactate, ATP production, and electron transport chain complex I activity.
- Real-time PCR and promoter studies assessed TR4's transcriptional regulation of NDUFAF1.
Main Results:
- TR4(-/-) mice exhibited mitochondrial myopathy, abnormal mitochondrial accumulation in soleus muscle, elevated serum lactate, and reduced mitochondrial ATP and complex I activity.
- Restoring TR4 in TR4(-/-) myoblasts rescued mitochondrial ATP generation and complex I activity.
- TR4 transcriptionally regulates NDUFAF1, a complex I assembly factor; NDUFAF1 restoration in TR4(-/-) myoblasts improved mitochondrial function.
Conclusions:
- TR4 plays a vital role in maintaining mitochondrial function, particularly in muscle tissue.
- Dysregulation of TR4 contributes to mitochondrial myopathy pathogenesis.
- Targeting TR4 with ligands or activators presents a potential therapeutic strategy for mitochondrial diseases.
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