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

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.