Complex I deficiency due to selective loss of Ndufs4 in the mouse heart results in severe hypertrophic cardiomyopathy.
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.
Department of Medicine, University of Cambridge, Cambridge, United Kingdom; MRC Mitochondrial Biology Unit, Cambridge, United Kingdom.
Edward T
ET
Chouchani
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Carmen
C
Methner
Wolfson Brain Imaging Centre, University of Cambridge, United Kingdom.
Guido
G
Buonincontri
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Chou-Hui
CH
Hu
MRC Mitochondrial Biology Unit, Cambridge, United Kingdom.
Angela
A
Logan
Wolfson Brain Imaging Centre, University of Cambridge, United Kingdom.
Stephen J
SJ
Sawiak
MRC Mitochondrial Biology Unit, Cambridge, United Kingdom.
Michael P
MP
Murphy
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Thomas
T
Krieg
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006352:Heart Ventricles / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012720:Severity of Illness Index
C534449:Ndufs4 protein, mouse; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I