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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Chouchani, Edward T 
Methner, Carmen 
Buonincontri, Guido 
Hu, Chou-Hui 
Logan, Angela 

Abstract

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.

Description

Keywords

Animals, 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

Journal Title

PLoS One

Conference Name

Journal ISSN

1932-6203
1932-6203

Volume Title

9

Publisher

Public Library of Science (PLoS)
Sponsorship
British Heart Foundation (None)
Medical Research Council (MC_U105663142)