Human Molecular Genetics Advance Access published online on September 29, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn310
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Mitochondrial Abnormalities in Spinal and Bulbar Muscular Atrophy
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
* To whom correspondence should be addressed at: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. Tel: 301-435-9288; Fax: 301-480-3365; Email: ranganas{at}ninds.nih.gov
Received August 4, 2008; Revised September 23, 2008; Accepted September 23, 2008
Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by polyglutamine expansion mutation in the androgen receptor. We investigated whether the mutant protein alters mitochondrial function. We found that constitutive and doxycycline-induced expression of the mutant androgen receptor in MN-1 and PC12 cells, respectively, are associated with depolarization of the mitochondrial membrane. This was mitigated by cyclosporine A, which inhibits opening of the mitochondrial permeability transition pore. We also found that expression of the mutant protein in the presence of ligand results in an elevated level of reactive oxygen species, which is blocked by treatment with the antioxidants co-enzyme Q10 and idebenone. The mutant protein in MN-1 cells also resulted in increased Bax, caspase 9 and caspase 3. We assessed the effects of mutant androgen receptor on the transcription of mitochondrial proteins and found altered expression of the peroxisome proliferator activated receptor 
coactivator 1 and the mitochondrial specific antioxidant superoxide dismutase-2 in affected tissues of SBMA knock-in mice. In addition, we found that the androgen receptor associates with mitochondria in cultured cells. This study thus provides evidence for mitochondrial dysfunction in SBMA cell and animal models, either through indirect effects on the transcription of nuclear-encoded mitochondrial genes or through direct effects of the mutant protein on mitochondria or both. These findings indicate possible benefit from mitochondrial therapy for SBMA.