title: 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.
authors.affiliation: Department of Pathology, University of Rochester, Medical Center, Rochester, New York 14646, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lee
authors.forename: Samuel
authors.initials: S
authors.lastname: Chou
authors.forename: Hideo
authors.initials: H
authors.lastname: Uno
authors.forename: Gonghui
authors.initials: G
authors.lastname: Li
authors.forename: Paul
authors.initials: P
authors.lastname: Brookes
authors.forename: Michael P
authors.initials: MP
authors.lastname: Massett
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
authors.forename: Lu-Min
authors.initials: LM
authors.lastname: Chen
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017240:Mitochondrial Myopathies / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D018908:Muscle Weakness / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal; D011987:Receptors, Steroid / Q000172:deficiency* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000172:deficiency* / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: C490514:Nr2c2 protein, mouse; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D012265:Ribonucleotides; D019344:Lactic Acid; D000620:Aminoimidazole Carboxamide; D000255:Adenosine Triphosphate; D008687:Metformin; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C031143:AICA ribonucleotide