Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors

Alessandra Zulian, Francesca Tagliavini, Erika Rizzo, Camilla Pellegrini, Francesca Sardone, Nicoletta Zini, Nadir Mario Maraldi, Spartaco Santi, Cesare Faldini, Luciano Merlini, Valeria Petronilli, Paolo Bernardi, Patrizia Sabatelli

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Article number324
JournalFrontiers in Aging Neuroscience
Volume6
Issue numberNOV
DOIs
Publication statusPublished - 2014

Fingerprint

Cyclophilins
Melanocytes
Mitochondria
Oligomycins
Collagen
Adenosine Triphosphate
Sarcopenia
Duchenne Muscular Dystrophy
Extracellular Matrix Proteins
Muscular Diseases
Permeability
Membrane Proteins
Skeletal Muscle
Bethlem myopathy
Scleroatonic muscular dystrophy
Biopsy
Muscles
Skin
Mutation
Pharmaceutical Preparations

Keywords

  • Collagen VI
  • Cyclophilin inhibitors
  • Melanocytes
  • Mitochondria
  • Muscular dystrophy
  • Permeability transition

ASJC Scopus subject areas

  • Ageing
  • Cognitive Neuroscience

Cite this

Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors. / Zulian, Alessandra; Tagliavini, Francesca; Rizzo, Erika; Pellegrini, Camilla; Sardone, Francesca; Zini, Nicoletta; Maraldi, Nadir Mario; Santi, Spartaco; Faldini, Cesare; Merlini, Luciano; Petronilli, Valeria; Bernardi, Paolo; Sabatelli, Patrizia.

In: Frontiers in Aging Neuroscience, Vol. 6, No. NOV, 324, 2014.

Research output: Contribution to journalArticle

Zulian, Alessandra ; Tagliavini, Francesca ; Rizzo, Erika ; Pellegrini, Camilla ; Sardone, Francesca ; Zini, Nicoletta ; Maraldi, Nadir Mario ; Santi, Spartaco ; Faldini, Cesare ; Merlini, Luciano ; Petronilli, Valeria ; Bernardi, Paolo ; Sabatelli, Patrizia. / Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors. In: Frontiers in Aging Neuroscience. 2014 ; Vol. 6, No. NOV.
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AU - Zulian, Alessandra

AU - Tagliavini, Francesca

AU - Rizzo, Erika

AU - Pellegrini, Camilla

AU - Sardone, Francesca

AU - Zini, Nicoletta

AU - Maraldi, Nadir Mario

AU - Santi, Spartaco

AU - Faldini, Cesare

AU - Merlini, Luciano

AU - Petronilli, Valeria

AU - Bernardi, Paolo

AU - Sabatelli, Patrizia

PY - 2014

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N2 - 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.

AB - 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.

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