Mitochondrial abnormalities in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by polyglutamine expansion mutation in the androgen receptor (AR). We investigated whether the mutant protein alters mitochondrial function. We found that constitutive and doxycycline-induced expression of the mutant AR 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 the expression of the mutant protein in the presence of ligand results in an elevated level of reactive oxygen species, which is blocked by the 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 AR on the transcription of mitochondrial proteins and found altered expression of the peroxisome proliferator-activated receptor gamma coactivator 1 and the mitochondrial specific antioxidant superoxide dismutase-2 in affected tissues of SBMA knock-in mice. In addition, we found that the AR 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.