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MITOCHONDRIA MORPHOLOGY AND THE ROLE OF PDE2 IN CARDIAC PATHOPHYSIOLOGY
  1. S Monterisi,
  2. M Zaccolo
  1. University of Oxford

Abstract

Mitochondria possess a highly dynamic morphology which can change to meet metabolic demands. Altered mitochondria morphology has been reported in a number of heart conditions where it may be linked to metabolic deficit of cardiac myocytes.

We have previously shown that phosphodiestarease 2 (PDE2), a cGMP activated enzyme that degrades both cAMP and cGMP, plays a key role in regulating cAMP signalling in the heart and is involved in the control of cardiac hypertrophy. We recently found that PDE2 localises to mitochondria. To investigate whether PDE2 plays a role in the regulation of mitochondrial dynamics, we used Mouse Embryonic Fibroblasts (MEF) from PDE2−/− embryos as a model system.

We found that homozygous PDE2−/− MEFs show longer, tubular mitochondria, whereas in wt MEFs cells mitochondria appear more fragmented, with PDE2+/− MEFs showing a mixed population. Quantitative analysis confirmed a significant difference in mitochondrial length in the three cell types. In line with these findings, PDE2 overexpression in PDE2−/− MEFs led to an increase in mitochondria fragmentation, whereas the expression in wt cells of a catalytically inactive mutant of PDE2 gave mitochondria with a more elongated morphology. Moreover, preliminary results on rat neonatal cardiac myocytes show that control cells have rounded clustered mitochondria whereas PDE2 knock down using siRNA results in more elongated mitochondria.

These results indicate that PDE2 may represent a key component of a cAMP signalling pathway localised at mitochondria and involved in regulation of mitochondria morphology and may have a role in regulating cardiac metabolism and energetics.

  • CARDIAC PROCEDURES AND THERAPY

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