title: Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors.
abstract: Ullrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI (ColVI) genes, which encode an extracellular matrix protein; yet, mitochondria play a major role in disease pathogenesis through a short circuit caused by inappropriate opening of the permeability transition pore, a high-conductance channel, which causes a shortage in ATP production. We find that melanocytes do not produce ColVI yet they bind it at the cell surface, suggesting that this protein may play a trophic role and that its absence may cause lesions similar to those seen in skeletal muscle. We show that mitochondria in melanocytes of Ullrich congenital muscular dystrophy and Bethlem myopathy patients display increased size, reduced matrix density, and disrupted cristae, findings that suggest a functional impairment. In keeping with this hypothesis, mitochondria (i) underwent anomalous depolarization after inhibition of the F-ATP synthase with oligomycin, and (ii) displayed decreased respiratory reserve capacity. The non-immunosuppressive cyclophilin inhibitor NIM811 prevented mitochondrial depolarization in response to oligomycin in melanocytes from both Ullrich congenital muscular dystrophy and Bethlem myopathy patients, and partially restored the respiratory reserve of melanocytes from one Bethlem myopathy patient. These results match our recent findings on melanocytes from patients affected by Duchenne muscular dystrophy (Pellegrini et al., 2013), and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in ColVI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia.
authors.affiliation: Department of Biomedical Sciences, University of Padova , Padova , Italy ; CNR Neuroscience Institute , Padova , Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zulian
authors.affiliation: CNR National Research Council of Italy, Institute of Molecular Genetics , Bologna , Italy ; SC Laboratory of Musculoskeletal Cell Biology, IOR , Bologna , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: Department of Biomedical Sciences, University of Padova , Padova , Italy ; CNR Neuroscience Institute , Padova , Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Rizzo
authors.affiliation: SC Laboratory of Musculoskeletal Cell Biology, IOR , Bologna , Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pellegrini
authors.affiliation: CNR National Research Council of Italy, Institute of Molecular Genetics , Bologna , Italy ; SC Laboratory of Musculoskeletal Cell Biology, IOR , Bologna , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sardone
authors.affiliation: CNR National Research Council of Italy, Institute of Molecular Genetics , Bologna , Italy ; SC Laboratory of Musculoskeletal Cell Biology, IOR , Bologna , Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Zini
authors.affiliation: CNR National Research Council of Italy, Institute of Molecular Genetics , Bologna , Italy.
authors.forename: Nadir Mario
authors.initials: NM
authors.lastname: Maraldi
authors.affiliation: CNR National Research Council of Italy, Institute of Molecular Genetics , Bologna , Italy ; SC Laboratory of Musculoskeletal Cell Biology, IOR , Bologna , Italy.
authors.forename: Spartaco
authors.initials: S
authors.lastname: Santi
authors.affiliation: Rizzoli Orthopaedic Institute, University of Bologna , Bologna , Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Faldini
authors.affiliation: SC Laboratory of Musculoskeletal Cell Biology, IOR , Bologna , Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.affiliation: Department of Biomedical Sciences, University of Padova , Padova , Italy ; CNR Neuroscience Institute , Padova , Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Petronilli
authors.affiliation: Department of Biomedical Sciences, University of Padova , Padova , Italy ; CNR Neuroscience Institute , Padova , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.affiliation: CNR National Research Council of Italy, Institute of Molecular Genetics , Bologna , Italy ; SC Laboratory of Musculoskeletal Cell Biology, IOR , Bologna , Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
keywords: collagen VI; cyclophilin inhibitors; melanocytes; mitochondria; muscular dystrophy; permeability transition