Article Text

PDF
068
THE ADULT MURINE HEART IS PROTECTED AGAINST ISCHEMIA-REPERFUSION INJURY IN THE ABSENCE OF BOTH MITOFUSIN (MFN) PROTEINS
  1. Andrew R Hall,
  2. Niall Burke,
  3. Rachel K Dongworth,
  4. Yun Chen,
  5. Gerald W Dorn,
  6. Derek J Hausenloy
  1. University College London, UK

Abstract

Background Cardiac-specific ablation of both Mfn1 and Mfn2 in the adult heart results in mitochondrial fragmentation and a lethal cardiomyopathy after about 6 weeks. The effect of combined Mfn1 and Mfn2 deletion on the susceptibility to acute ischemia-reperfusion injury (IRI) and subsequent calcium overload is not known, and is investigated in this study.

Methods and Results Cardiac-specific ablation of both Mfn1 and Mfn2 (DKO) was initiated in mice aged 5 weeks using 5 days administration of tamoxifen (MerCreMer), resulting in total knockout of both these proteins at the age of 10 weeks. These mice were subjected to in vivo myocardial ischemia (30 mins) followed by 24 hrs reperfusion before myocardial infarct size was determined. The sustained MI size in the DKO mice was 50% smaller than that in the WT control mice. These findings were associated with decreased MPTP opening susceptibility (assessed by calcium-induced mitochondrial swelling), reduced mitochondrial calcium overload after simulated IR (assessed by Rhod2 staining) and impaired mitochondrial respiration in the DKO hearts when compared to WT control.

Conclusions We have shown that the adult murine heart deficient in both Mfn1 and Mfn2 was protected against acute IRI, a finding which was associated with defects in mitochondrial function and reduced mitochondrial calcium overload. This data suggests that the Mitofusins may be therapeutic targets for cardioprotection.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.