Enhanced oxidative stress sensitizes the mitochondrial permeability transition pore to opening in heart from Zucker Fa/fa rats with type 2 diabetes uri icon


  • © 2015 Elsevier Inc.Aims Obesity and diabetes mellitus type 2 (DM2) frequently coexist and increase the propensity of cardiovascular dysfunction by numerous mechanisms. Chief among them are oxidative stress and Ca2 + dysregulation, and both are inducers of the mitochondrial permeability transition pore (MPTP). Nevertheless, it is unknown whether MPTP formation is triggered in DM2 animals, and thereby contributing to cardiac dysfunction. We assessed MPTP sensitivity and reactive oxygen species production in cardiac mitochondria, as well as cytosolic Ca2 + handling in ventricular myocytes from rats with DM2. Main methods Male Zucker Fa/fa rats (Fa/fa) 32 weeks old presenting DM2, concentric hypertrophy, and diastolic dysfunction were used. MPTP formation was evaluated in isolated mitochondria and Ca2 + handling in ventricular myocytes, by spectrophotometric and confocal microscope techniques, respectively. Key findings We found that the systolic Ca2 + transient relaxation was ~ 40% slower, while mitochondrial H2O2 production increased by ~ 6-fold. MPTP opening in isolated mitochondria from Fa/fa (mFa/fa) was more sensitive to Ca2 + than in mitochondria from lean rats (mLean), and correlated with increased thiol group exposure. The mFa/fa showed decreased oxidative phosphorylation capacity. The ATP content decreased in myocytes, while the PCr/ATP ratio remained unchanged and caspase 9 activity largely increased in myocytes from Fa/fa animals. Significance Our results showed that oxidative stress and diastolic Ca2 + dysregulation increased MPTP sensitivity leading to mitochondrial dysfunction and apoptosis. Mitochondrial dysfunction could compromise ATP synthesis, and lower ATP could be linked to decreased SERCA2 activity, which might underlie diastolic dysfunction. Prolonged Ca2 + transients might further exacerbate mitochondrial dysfunction.

Publication date

  • November 15, 2015