title: Mitochondrial implications in bulbospinal muscular atrophy (Kennedy disease).
abstract: There is increasing evidence that mitochondrial functions are secondarily disturbed in bulbospinal muscular atrophy (BSMA). This review focuses on the relation between BSMA and the effect of the expanded polyglutamine (poly-Q) androgen receptor (AR) on mitochondrial functions. Mitochondrial functions in bulbospinal muscular atrophy (SBMA) are affected on the molecular, clinical, and therapeutic level. On the molecular level there is down-regulation of various nuclear-DNA-encoded mitochondrial proteins by mutant androgen receptor (mAR), colocalization of the mAR with various mitochondrial proteins, association of mAR aggregates with mitochondria resulting in abnormal distribution of mitochondria, mtDNA depletion or multiple mtDNA deletions, mitochondrial membrane depolarization, increase in reactive oxidative species, and activation of the mitochondrial caspase pathway. On the clinical level various mitochondrial disorders mimic SBMA, and on the therapeutic level pioglitazone expresses PPAR-γ, cyclosporine-A restores mitochondrial membrane potentials, coenzyme-Q and idebenone reduce oxidative stress, and geldanamycin up-regulates protective mitochondrial heat shock proteins. In conclusion, in BSMA mitochondrial dysfunction results from various interactions of elongated poly-Q AR with mitochondria, mitochondrial proteins, nuclear or mitochondrial DNA, causing oxidative stress, decreased mitochondrial membrane potential, or activation of the mitochondrial caspase pathway. Additionally, mitochondrial disease may mimic BSMA and therapeutic approaches may depend on modifications of mitochondrial pathways.
authors.affiliation: a Krankenanstalt Rudolfstiftung , Vienna , Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Finsterer
authors.affiliation: b All India Institute of Medical Sciences , Delhi , India.
authors.forename: Anushree
authors.initials: A
authors.lastname: Mishra
authors.affiliation: c Department of Genetics , King Faisal Specialist Hospital and Research Centre , Riyadh , Saudi Arabia.
authors.forename: Salma
authors.initials: S
authors.lastname: Wakil
authors.affiliation: d Dulbecco Telethon Institute Laboratory of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO) , University of Trento , Trento.
authors.forename: Maria
authors.initials: M
authors.lastname: Pennuto
authors.affiliation: e Department of Neurosciences , University of Padova , Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Soraru
mesh_terms: D055534:Bulbo-Spinal Atrophy, X-Linked / Q000473:pathology* / Q000503:physiopathology*; D019317:Evidence-Based Medicine; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological
chemical_list: D024101:Mitochondrial Proteins
keywords: Mitochondrial disorder; X-linked spinal muscular atrophy; bulbospinal neuronopathy; mitochondrial DNA; motor neuron disease; spinobulbar muscular atrophy