Mitochondrial complex I dysfunction and altered NAD(P)H kinetics in rat myocardium in cardiac right ventricular hypertrophy and failure

Rob C I Wüst, Heder J de Vries, Liesbeth T Wintjes, Richard J Rodenburg, Hans W M Niessen, Ger J M Stienen

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

AIMS: In cardiac hypertrophy (CH) and heart failure (HF), alterations occur in mitochondrial enzyme content and activities but the origin and implications of these changes for mitochondrial function need to be resolved.

METHODS AND RESULTS: Right ventricular CH or HF was induced by monocrotaline injection, which causes pulmonary artery hypertension, in rats. Results were compared with saline injection (CON). NAD(P)H and FAD autofluorescence were recorded in thin intact cardiac trabeculae during transitions in stimulation frequency, to assess mitochondrial complex I and complex II function, respectively. Oxygen consumption, mitochondrial morphology, protein content, and enzymatic activity were assessed. NAD(P)H autofluorescence upon an increase in stimulation frequency showed a rapid decline followed by a slow recovery. FAD autofluorescence followed a similar time course, but in opposite direction. The amplitude of the early rapid change in NAD(P)H autofluorescence was severely depressed in CH and HF compared with CON. The rapid changes in FAD autofluorescence in CH and HF were reduced to a lesser extent. Complex I-coupled respiration showed an ∼3.5-fold reduction in CH and HF; complex II-coupled respiration was depressed two-fold in HF. Western blot analyses revealed modest reductions in complex I protein content in CH and HF and in complex I activity in supercomplexes in HF. Mitochondrial volume density was similar, but mitochondrial remodelling was evident from changes in ultrastructure and fusion/fission indices in CH and HF.

CONCLUSION: These results suggest that the alterations in mitochondrial function observed in right ventricular CH and HF can be mainly attributed to complex I dysfunction.

Original languageEnglish
Pages (from-to)362-72
Number of pages11
JournalCardiovascular Research
Volume111
Issue number4
DOIs
Publication statusPublished - Sep 2016

Keywords

  • Animals
  • Cardiomegaly/metabolism
  • Disease Models, Animal
  • Heart/physiopathology
  • Hypertrophy, Right Ventricular/metabolism
  • Male
  • Mitochondria/metabolism
  • Myocardium/metabolism
  • NAD/metabolism
  • NADP/metabolism
  • Oxygen Consumption/physiology
  • Rats, Wistar

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