TY - JOUR
T1 - Mice lacking TR4 nuclear receptor develop mitochondrial myopathy with deficiency in complex I
AU - Liu, Su
AU - Lee, Yi Fen
AU - Chou, Samuel
AU - Uno, Hideo
AU - Li, Gonghui
AU - Brookes, Paul
AU - Massett, Michael P.
AU - Wu, Qiao
AU - Chen, Lu Min
AU - Chang, Chawnshang
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/8/1
Y1 - 2011/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79961000873&partnerID=8YFLogxK
U2 - 10.1210/me.2010-0455
DO - 10.1210/me.2010-0455
M3 - Article
C2 - 21622535
AN - SCOPUS:79961000873
VL - 25
SP - 1301
EP - 1310
JO - Molecular Endocrinology
JF - Molecular Endocrinology
SN - 0888-8809
IS - 8
ER -