Mitochondrial DNA Variation Dictates Expressivity and Progression of Nuclear DNA Mutations Causing Cardiomyopathy

Cell Metabolism
Meagan J McManusDouglas C Wallace

Abstract

Nuclear-encoded mutations causing metabolic and degenerative diseases have highly variable expressivity. Patients sharing the homozygous mutation (c.523delC) in the adenine nucleotide translocator 1 gene (SLC25A4, ANT1) develop cardiomyopathy that varies from slowly progressive to fulminant. This variability correlates with the mitochondrial DNA (mtDNA) lineage. To confirm that mtDNA variants can modulate the expressivity of nuclear DNA (nDNA)-encoded diseases, we combined in mice the nDNA Slc25a4-/- null mutation with a homoplasmic mtDNA ND6P25L or COIV421A variant. The ND6P25L variant significantly increased the severity of cardiomyopathy while the COIV421A variant was phenotypically neutral. The adverse Slc25a4-/- and ND6P25L combination was associated with impaired mitochondrial complex I activity, increased oxidative damage, decreased l-Opa1, altered mitochondrial morphology, sensitization of the mitochondrial permeability transition pore, augmented somatic mtDNA mutation levels, and shortened lifespan. The strikingly different phenotypic effects of these mild mtDNA variants demonstrate that mtDNA can be an important modulator of autosomal disease.

References

Nov 12, 1998·The American Journal of Pathology·E ArbustiniM Viganò
Feb 2, 2002·The EMBO Journal·Patrick PaumardJean Velours
Apr 9, 2002·The Journal of Biological Chemistry·Nagendra YadavaImmo E Scheffler
Jan 30, 2003·Human Molecular Genetics·Rebeca Acín-PérezJosé Antonio Enríquez
Aug 4, 2005·The Biochemical Journal·Martin D BrandEmma J Cornwall
Dec 21, 2005·Annals of Neurology·Rosalba CarrozzoHermann Schägger
Feb 25, 2006·Human Molecular Genetics·Ting-Ting HuangCharles J Epstein
Mar 2, 2006·Molecular Interventions·Sue Piper DucklesVincent Procaccio
Mar 6, 2007·Nature Genetics·Marc VermulstLawrence A Loeb
Mar 4, 2008·Nature Genetics·Marc VermulstLawrence A Loeb
Mar 8, 2008·The EMBO Journal·Mike StraussWerner Kühlbrandt
Oct 25, 2008·Methods : a Companion to Methods in Enzymology·Marc VermulstLawrence A Loeb
Dec 9, 2008·The Biochemical Journal·Michael P Murphy
Jan 13, 2010·Experimental Gerontology·Martin D Brand
Mar 2, 2010·Biochimica Et Biophysica Acta·Ilka WittigHermann Schägger
Apr 7, 2010·Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography·Holly GeyerPartho P Sengupta
Oct 19, 2010·Biochimica Et Biophysica Acta·Arnaud ChevrollierGeorges Stepien
Oct 28, 2010·European Journal of Human Genetics : EJHG·Michael V ZaragozaDouglas C Wallace
Nov 12, 2010·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Aekyong KimTing-Ting Huang
Dec 24, 2010·The Journal of Experimental Biology·Barbara Cannon, Jan Nedergaard
May 24, 2011·Progress in Pediatric Cardiology·George A PorterShey-Shing Sheu
Dec 22, 2011·Journal of Medical Genetics·Andoni Echaniz-LagunaBénédicte Mousson de Camaret
Feb 23, 2012·Scientific Reports·Riekelt H HoutkooperJohan Auwerx
Mar 3, 2012·G3 : Genes - Genomes - Genetics·Stefanie J NavarroGrant R Macgregor
Apr 21, 2012·Proceedings of the National Academy of Sciences of the United States of America·Fuyun JiDouglas C Wallace
Aug 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Karen M DaviesWerner Kühlbrandt
Nov 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Chun Shi LinDouglas C Wallace

❮ Previous
Next ❯

Citations

Dec 28, 2018·Physiology International·A YabluchanskiyS Tarantini
Aug 6, 2019·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Bérénice A Benayoun, Changhan Lee
Oct 31, 2019·BMC Genomics·Jukka KiiskiläKari Majamaa
Dec 4, 2019·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·David M Rand, Jim A Mossman
May 16, 2019·International Journal of Molecular Sciences·Misa HiroseSaleh M Ibrahim
Mar 7, 2020·Communications Biology·Kenichi YamamotoYukinori Okada
Jan 31, 2020·Human Genetics·Joseph C ReynoldsChanghan Lee
Sep 30, 2020·Nature Reviews. Genetics·James B Stewart, Patrick F Chinnery
Oct 26, 2020·Journal of Inherited Metabolic Disease·James Bruce Stewart
Dec 15, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Lin ZhaoYa Cao
Dec 29, 2020·Biochimica Et Biophysica Acta. General Subjects·Kaori Ishikawa, Kazuto Nakada
Jan 31, 2021·Nature Communications·Zhan YinJudy Hirst
Jan 11, 2021·Trends in Cell Biology·Alexander J SercelMichael A Teitell
Jun 21, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Marta Luna-SanchezCarlo Viscomi
Jul 16, 2021·The Journal of Biological Chemistry·Qiufen HeMin-Xin Guan

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.

Related Papers

Biomedical Reports
Josef Finsterer, Sinda Zarrouk-Mahjoub
Environmental and Molecular Mutagenesis
Douglas C Wallace
© 2022 Meta ULC. All rights reserved