Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors
Ullrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI 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 por...
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2014-11-01
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doaj-9fdf9e66f4dd4f39a602136a555298572020-11-24T23:48:35ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652014-11-01610.3389/fnagi.2014.00324108835Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitorsAlessandra eZulian0Francesca eTagliavini1Francesca eTagliavini2Erika eRizzo3Erika eRizzo4Camilla ePellegrini5Francesca eSardone6Francesca eSardone7Nicoletta eZini8Nicoletta eZini9Nadir Mario Maraldi10Spartaco eSanti11Spartaco eSanti12Cesare eFaldini13Luciano eMerlini14Valeria ePetronilli15Valeria ePetronilli16Paolo eBernardi17Paolo eBernardi18Patrizia eSabatelli19Patrizia eSabatelli20University of PadovaConsiglio Nazionale delle RicercheIstituto Ortopedico RizzoliUniversity of PadovaConsiglio Nazionale delle RicercheIstituto Ortopedico RizzoliConsiglio Nazionale delle RicercheIstituto Ortopedico RizzoliConsiglio Nazionale delle RicercheIstituto Ortopedico RizzoliIstituto Ortopedico RizzoliConsiglio Nazionale delle RicercheIstituto Ortopedico RizzoliIstituto Ortopedico RizzoliIstituto Ortopedico RizzoliUniversity of PadovaConsiglio Nazionale delle RicercheUniversity of PadovaConsiglio Nazionale delle RicercheConsiglio Nazionale delle RicercheIstituto Ortopedico RizzoliUllrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI 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 collagen VI 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 myooathy 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 Melanocytes--a novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy. J Cell Physiol 228, 1323-1331), and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in collagen VI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia.http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00324/fullMelanocytesMitochondriapermeability transitionmuscular dystrophycollagen VIcyclophilin inhibitors |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alessandra eZulian Francesca eTagliavini Francesca eTagliavini Erika eRizzo Erika eRizzo Camilla ePellegrini Francesca eSardone Francesca eSardone Nicoletta eZini Nicoletta eZini Nadir Mario Maraldi Spartaco eSanti Spartaco eSanti Cesare eFaldini Luciano eMerlini Valeria ePetronilli Valeria ePetronilli Paolo eBernardi Paolo eBernardi Patrizia eSabatelli Patrizia eSabatelli |
spellingShingle |
Alessandra eZulian Francesca eTagliavini Francesca eTagliavini Erika eRizzo Erika eRizzo Camilla ePellegrini Francesca eSardone Francesca eSardone Nicoletta eZini Nicoletta eZini Nadir Mario Maraldi Spartaco eSanti Spartaco eSanti Cesare eFaldini Luciano eMerlini Valeria ePetronilli Valeria ePetronilli Paolo eBernardi Paolo eBernardi Patrizia eSabatelli Patrizia eSabatelli Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors Frontiers in Aging Neuroscience Melanocytes Mitochondria permeability transition muscular dystrophy collagen VI cyclophilin inhibitors |
author_facet |
Alessandra eZulian Francesca eTagliavini Francesca eTagliavini Erika eRizzo Erika eRizzo Camilla ePellegrini Francesca eSardone Francesca eSardone Nicoletta eZini Nicoletta eZini Nadir Mario Maraldi Spartaco eSanti Spartaco eSanti Cesare eFaldini Luciano eMerlini Valeria ePetronilli Valeria ePetronilli Paolo eBernardi Paolo eBernardi Patrizia eSabatelli Patrizia eSabatelli |
author_sort |
Alessandra eZulian |
title |
Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors |
title_short |
Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors |
title_full |
Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors |
title_fullStr |
Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors |
title_full_unstemmed |
Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors |
title_sort |
melanocytes from patients affected by ullrich congenital muscular dystrophy and bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Aging Neuroscience |
issn |
1663-4365 |
publishDate |
2014-11-01 |
description |
Ullrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI 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 collagen VI 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 myooathy 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 Melanocytes--a novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy. J Cell Physiol 228, 1323-1331), and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in collagen VI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia. |
topic |
Melanocytes Mitochondria permeability transition muscular dystrophy collagen VI cyclophilin inhibitors |
url |
http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00324/full |
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