Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review

Background: Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause mitochondrial disease (MitD), a clinically heterogeneous group of disorders that often present with neuropsychiatric s...

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Authors: Valiente Pallejà, Alba, Tortajada, Juan, Bulduk, Bengisu K., Vilella, Elisabet, Garrabou Tornos, Glòria, Muntané, Gerard, Martorell, Lourdes
Format: article
Status:Published version
Publication Date:2022
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/209139
Online Access:https://hdl.handle.net/2445/209139
Access Level:Open access
Keyword:ADN mitocondrial
Malalties cerebrals
Envelliment cerebral
Lesions cerebrals
Mitochondrial DNA
Brain diseases
Aging brain
Brain damage
id ES_e2fa54712cbfbd0273e64b9abdaed05d
oai_identifier_str oai:diposit.ub.edu:2445/209139
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review
title Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review
spellingShingle Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review
Valiente Pallejà, Alba
ADN mitocondrial
Malalties cerebrals
Envelliment cerebral
Lesions cerebrals
Mitochondrial DNA
Brain diseases
Aging brain
Brain damage
title_short Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review
title_full Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review
title_fullStr Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review
title_full_unstemmed Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review
title_sort Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review
dc.creator.none.fl_str_mv Valiente Pallejà, Alba
Tortajada, Juan
Bulduk, Bengisu K.
Vilella, Elisabet
Garrabou Tornos, Glòria
Muntané, Gerard
Martorell, Lourdes
author Valiente Pallejà, Alba
author_facet Valiente Pallejà, Alba
Tortajada, Juan
Bulduk, Bengisu K.
Vilella, Elisabet
Garrabou Tornos, Glòria
Muntané, Gerard
Martorell, Lourdes
author_role author
author2 Tortajada, Juan
Bulduk, Bengisu K.
Vilella, Elisabet
Garrabou Tornos, Glòria
Muntané, Gerard
Martorell, Lourdes
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv ADN mitocondrial
Malalties cerebrals
Envelliment cerebral
Lesions cerebrals
Mitochondrial DNA
Brain diseases
Aging brain
Brain damage
topic ADN mitocondrial
Malalties cerebrals
Envelliment cerebral
Lesions cerebrals
Mitochondrial DNA
Brain diseases
Aging brain
Brain damage
description Background: Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause mitochondrial disease (MitD), a clinically heterogeneous group of disorders that often present with neuropsychiatric symptoms. Understanding the nature and frequency of mtDNA alterations in health and disease could be a cornerstone in disentangling the relationship between biochemical findings and clinical symptoms of brain disorders. This systematic review aimed to summarize the mtDNA alterations in human brain tissue reported to date that have implications for further research on the pathophysiological significance of mtDNA alterations in brain functioning. Methods: We searched the PubMed and Embase databases using distinct terms related to postmortem human brain and mtDNA up to June 10, 2021. Reports were eligible if they were empirical studies analysing mtDNA in postmortem human brains. Findings: A total of 158 of 637 studies fulfilled the inclusion criteria and were clustered into the following groups: MitD (48 entries), neurological diseases (NeuD, 55 entries), psychiatric diseases (PsyD, 15 entries), a miscellaneous group with controls and other clinical diseases (5 entries), ageing (20 entries), and technical issues (5 entries). Ten entries were ascribed to more than one group. Pathogenic single nucleotide variants (pSNVs), both homo- or heteroplasmic variants, have been widely reported in MitD, with heteroplasmy levels varying among brain regions; however, pSNVs are rarer in NeuD, PsyD and ageing. A lower mtDNA copy number (CN) in disease was described in most, but not all, of the identified studies. mtDNA deletions were identified in individuals in the four clinical categories and ageing. Notably, brain samples showed significantly more mtDNA deletions and at higher heteroplasmy percentages than blood samples, and several of the deletions present in the brain were not detected in the blood. Finally, mtDNA heteroplasmy, mtDNA CN and the deletion levels varied depending on the brain region studied. Interpretation: mtDNA alterations are well known to affect human tissues, including the brain. In general, we found that studies of MitD, NeuD, PsyD, and ageing were highly variable in terms of the type of disease or ageing process investigated, number of screened individuals, studied brain regions and technology used. In NeuD and PsyD, no particular type of mtDNA alteration could be unequivocally assigned to any specific disease or diagnostic group. However, the presence of mtDNA deletions and mtDNA CN variation imply a role for mtDNA in NeuD and PsyD. Heteroplasmy levels and threshold effects, affected brain regions, and mitotic segregation patterns of mtDNA alterations may be involved in the complex inheritance of NeuD and PsyD and in the ageing process. Therefore, more information is needed regarding the type of mtDNA alteration, the affected brain regions, the heteroplasmy levels, and their relationship with clinical phenotypes and the ageing process. Funding: Hospital Universitari Institut Pere Mata; Institut d'Investigació Sanitària Pere Virgili; Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (PI18/00514).
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/209139
url https://hdl.handle.net/2445/209139
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.ebiom.2022.103815
EBioMedicine, 2022, vol. 76
https://doi.org/10.1016/j.ebiom.2022.103815
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Valiente Pallejà, Alba et al., 2022
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Valiente Pallejà, Alba et al., 2022
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869422459952824320
spelling Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic reviewValiente Pallejà, AlbaTortajada, JuanBulduk, Bengisu K.Vilella, ElisabetGarrabou Tornos, GlòriaMuntané, GerardMartorell, LourdesADN mitocondrialMalalties cerebralsEnvelliment cerebralLesions cerebralsMitochondrial DNABrain diseasesAging brainBrain damageBackground: Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause mitochondrial disease (MitD), a clinically heterogeneous group of disorders that often present with neuropsychiatric symptoms. Understanding the nature and frequency of mtDNA alterations in health and disease could be a cornerstone in disentangling the relationship between biochemical findings and clinical symptoms of brain disorders. This systematic review aimed to summarize the mtDNA alterations in human brain tissue reported to date that have implications for further research on the pathophysiological significance of mtDNA alterations in brain functioning. Methods: We searched the PubMed and Embase databases using distinct terms related to postmortem human brain and mtDNA up to June 10, 2021. Reports were eligible if they were empirical studies analysing mtDNA in postmortem human brains. Findings: A total of 158 of 637 studies fulfilled the inclusion criteria and were clustered into the following groups: MitD (48 entries), neurological diseases (NeuD, 55 entries), psychiatric diseases (PsyD, 15 entries), a miscellaneous group with controls and other clinical diseases (5 entries), ageing (20 entries), and technical issues (5 entries). Ten entries were ascribed to more than one group. Pathogenic single nucleotide variants (pSNVs), both homo- or heteroplasmic variants, have been widely reported in MitD, with heteroplasmy levels varying among brain regions; however, pSNVs are rarer in NeuD, PsyD and ageing. A lower mtDNA copy number (CN) in disease was described in most, but not all, of the identified studies. mtDNA deletions were identified in individuals in the four clinical categories and ageing. Notably, brain samples showed significantly more mtDNA deletions and at higher heteroplasmy percentages than blood samples, and several of the deletions present in the brain were not detected in the blood. Finally, mtDNA heteroplasmy, mtDNA CN and the deletion levels varied depending on the brain region studied. Interpretation: mtDNA alterations are well known to affect human tissues, including the brain. In general, we found that studies of MitD, NeuD, PsyD, and ageing were highly variable in terms of the type of disease or ageing process investigated, number of screened individuals, studied brain regions and technology used. In NeuD and PsyD, no particular type of mtDNA alteration could be unequivocally assigned to any specific disease or diagnostic group. However, the presence of mtDNA deletions and mtDNA CN variation imply a role for mtDNA in NeuD and PsyD. Heteroplasmy levels and threshold effects, affected brain regions, and mitotic segregation patterns of mtDNA alterations may be involved in the complex inheritance of NeuD and PsyD and in the ageing process. Therefore, more information is needed regarding the type of mtDNA alteration, the affected brain regions, the heteroplasmy levels, and their relationship with clinical phenotypes and the ageing process. Funding: Hospital Universitari Institut Pere Mata; Institut d'Investigació Sanitària Pere Virgili; Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (PI18/00514).Elsevier2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/209139Articles publicats en revistes (Medicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.ebiom.2022.103815EBioMedicine, 2022, vol. 76https://doi.org/10.1016/j.ebiom.2022.103815cc-by-nc-nd (c) Valiente Pallejà, Alba et al., 2022http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2091392026-05-27T06:46:51Z
score 15,300719

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