Complex I deficiency due to selective loss of Ndufs4 in the mouse heart results in severe hypertrophic cardiomyopathy.

TitleComplex I deficiency due to selective loss of Ndufs4 in the mouse heart results in severe hypertrophic cardiomyopathy.
Publication TypeJournal Article
Year of Publication2014
AuthorsChouchani, ET, Methner, C, Buonincontri, G, Hu, C-H, Logan, A, Sawiak, SJ, Murphy, MP, Krieg, T
JournalPLoS One
Date Published2014
KeywordsAnimals, Apoptosis, Cardiomyopathy, Hypertrophic, Disease Models, Animal, Electron Transport Complex I, Enzyme Activation, Female, Heart Ventricles, Hydrogen Peroxide, Magnetic Resonance Imaging, Cine, Male, Mice, Mice, Knockout, Mitochondria, Heart, Reactive Oxygen Species, Severity of Illness Index

Mitochondrial complex I, the primary entry point for electrons into the mitochondrial respiratory chain, is both critical for aerobic respiration and a major source of reactive oxygen species. In the heart, chronic dysfunction driving cardiomyopathy is frequently associated with decreased complex I activity, from both genetic and environmental causes. To examine the functional relationship between complex I disruption and cardiac dysfunction we used an established mouse model of mild and chronic complex I inhibition through heart-specific Ndufs4 gene ablation. Heart-specific Ndufs4-null mice had a decrease of ∼ 50% in complex I activity within the heart, and developed severe hypertrophic cardiomyopathy as assessed by magnetic resonance imaging. The decrease in complex I activity, and associated cardiac dysfunction, occurred absent an increase in mitochondrial hydrogen peroxide levels in vivo, accumulation of markers of oxidative damage, induction of apoptosis, or tissue fibrosis. Taken together, these results indicate that diminished complex I activity in the heart alone is sufficient to drive hypertrophic cardiomyopathy independently of alterations in levels of mitochondrial hydrogen peroxide or oxidative damage.

Alternate JournalPLoS ONE
Citation Key10.1371/journal.pone.0094157
PubMed ID24705922
PubMed Central IDPMC3976382
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
PG/12/42/29655 / / British Heart Foundation / United Kingdom
/ / Canadian Institutes of Health Research / Canada