MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile

Detalhes bibliográficos
Autor(a) principal: Jacinto, Sandra
Data de Publicação: 2021
Outros Autores: Guerreiro, Patrícia, Oliveira, Rita Machado de, Oliveira, Teresa Cunha, Santos, Maria João, Grazina, Manuela, Rego, A. Cristina, Outeiro, Tiago F.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/103965
https://doi.org/10.3389/fncel.2021.641264
Resumo: Mutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.
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spelling MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic ProfileMpv17 mutationsmitochondrial depletion syndromemitochondrial dysfunctionprotein mislocationneurode generationMutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.Frontiers Media S.A.2021info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/103965http://hdl.handle.net/10316/103965https://doi.org/10.3389/fncel.2021.641264eng1662-5102Jacinto, SandraGuerreiro, PatríciaOliveira, Rita Machado deOliveira, Teresa CunhaSantos, Maria JoãoGrazina, ManuelaRego, A. CristinaOuteiro, Tiago F.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-12-12T21:37:59Zoai:estudogeral.uc.pt:10316/103965Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:20:42.512826Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile
title MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile
spellingShingle MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile
Jacinto, Sandra
Mpv17 mutations
mitochondrial depletion syndrome
mitochondrial dysfunction
protein mislocation
neurode generation
title_short MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile
title_full MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile
title_fullStr MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile
title_full_unstemmed MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile
title_sort MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile
author Jacinto, Sandra
author_facet Jacinto, Sandra
Guerreiro, Patrícia
Oliveira, Rita Machado de
Oliveira, Teresa Cunha
Santos, Maria João
Grazina, Manuela
Rego, A. Cristina
Outeiro, Tiago F.
author_role author
author2 Guerreiro, Patrícia
Oliveira, Rita Machado de
Oliveira, Teresa Cunha
Santos, Maria João
Grazina, Manuela
Rego, A. Cristina
Outeiro, Tiago F.
author2_role author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Jacinto, Sandra
Guerreiro, Patrícia
Oliveira, Rita Machado de
Oliveira, Teresa Cunha
Santos, Maria João
Grazina, Manuela
Rego, A. Cristina
Outeiro, Tiago F.
dc.subject.por.fl_str_mv Mpv17 mutations
mitochondrial depletion syndrome
mitochondrial dysfunction
protein mislocation
neurode generation
topic Mpv17 mutations
mitochondrial depletion syndrome
mitochondrial dysfunction
protein mislocation
neurode generation
description Mutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/103965
http://hdl.handle.net/10316/103965
https://doi.org/10.3389/fncel.2021.641264
url http://hdl.handle.net/10316/103965
https://doi.org/10.3389/fncel.2021.641264
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1662-5102
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv Frontiers Media S.A.
publisher.none.fl_str_mv Frontiers Media S.A.
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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