ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiency
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Outros Autores: | , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/215302 |
Resumo: | Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsu ciency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics–metabolomics). The data showed that Adck2+/ mice exhibited impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in Coenzyme Q (CoQ) biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation. |
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Matté, CristianeVázquez-Fonseca, LuisNavas, Plácido2020-11-20T04:15:33Z20192077-0383http://hdl.handle.net/10183/215302001116275Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsu ciency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics–metabolomics). The data showed that Adck2+/ mice exhibited impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in Coenzyme Q (CoQ) biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation.application/pdfengJournal of clinical medicine. Basel. Vol. 8, no. 9 (Sep. 2019), 1374, 22 p.Ácidos graxosGlucoseUbiquinonaMiopatias mitocondriaisProteínas mitocondriaisCoenzyme Q deficiencyMitochondrial diseaseRespiratory chainFatty acidsMyopathyaarF domain-containing mitochondrial protein kinase 2(ADCK2)ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiencyEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001116275.pdf.txt001116275.pdf.txtExtracted Texttext/plain85654http://www.lume.ufrgs.br/bitstream/10183/215302/2/001116275.pdf.txt1f258824c7540e4c6e44907db19077ddMD52ORIGINAL001116275.pdfTexto completo (inglês)application/pdf2303660http://www.lume.ufrgs.br/bitstream/10183/215302/1/001116275.pdf5bdc7be27a7944c9cd7a9517d6cc58beMD5110183/2153022021-03-09 04:39:47.008031oai:www.lume.ufrgs.br:10183/215302Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2021-03-09T07:39:47Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiency |
title |
ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiency |
spellingShingle |
ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiency Matté, Cristiane Ácidos graxos Glucose Ubiquinona Miopatias mitocondriais Proteínas mitocondriais Coenzyme Q deficiency Mitochondrial disease Respiratory chain Fatty acids Myopathy aarF domain-containing mitochondrial protein kinase 2(ADCK2) |
title_short |
ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiency |
title_full |
ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiency |
title_fullStr |
ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiency |
title_full_unstemmed |
ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiency |
title_sort |
ADCK2 haploinsuciency reduces mitochondrial lipid oxidation and causes myopathy associated with CoQ deficiency |
author |
Matté, Cristiane |
author_facet |
Matté, Cristiane Vázquez-Fonseca, Luis Navas, Plácido |
author_role |
author |
author2 |
Vázquez-Fonseca, Luis Navas, Plácido |
author2_role |
author author |
dc.contributor.author.fl_str_mv |
Matté, Cristiane Vázquez-Fonseca, Luis Navas, Plácido |
dc.subject.por.fl_str_mv |
Ácidos graxos Glucose Ubiquinona Miopatias mitocondriais Proteínas mitocondriais |
topic |
Ácidos graxos Glucose Ubiquinona Miopatias mitocondriais Proteínas mitocondriais Coenzyme Q deficiency Mitochondrial disease Respiratory chain Fatty acids Myopathy aarF domain-containing mitochondrial protein kinase 2(ADCK2) |
dc.subject.eng.fl_str_mv |
Coenzyme Q deficiency Mitochondrial disease Respiratory chain Fatty acids Myopathy aarF domain-containing mitochondrial protein kinase 2(ADCK2) |
description |
Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsu ciency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics–metabolomics). The data showed that Adck2+/ mice exhibited impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in Coenzyme Q (CoQ) biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation. |
publishDate |
2019 |
dc.date.issued.fl_str_mv |
2019 |
dc.date.accessioned.fl_str_mv |
2020-11-20T04:15:33Z |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
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publishedVersion |
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http://hdl.handle.net/10183/215302 |
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2077-0383 |
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001116275 |
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2077-0383 001116275 |
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http://hdl.handle.net/10183/215302 |
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eng |
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eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
Journal of clinical medicine. Basel. Vol. 8, no. 9 (Sep. 2019), 1374, 22 p. |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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