Overexpression of mitofusin 2 in the diabetic heart; pathological or cardioprotective remodelling?

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Background: Mitochondrial dysfunction is an established hallmark of diabetic cardiomyopathy (DCM). Mitofusin 2 (Mfn2) is widely believed to function as a molecular tether, binding mitochondria to the sarcoplasmic reticulum (SR) to form specialised Ca2+ microdomains [1, 2]. However, recent conflicting data suggests a more complex function for Mfn2 [3]. Loss of Mfn2 function has been shown to reduce glucose oxidation and mitochondrial membrane potential leading to the assumption that down-regulation of Mfn2 is linked to a pathophysiological response. However, the role of Mfn2 in the heart is poorly characterised. Employing cardiac cell models and a type 1 model of diabetes, we investigate the role of Mfn2 in the heart and how it is modulated in response to pathological stimuli associated with diabetes.
Methods and results: Protein expression levels were measured in control and streptozotocin-treated (STZ) Wistar rat heart using western blot. Cell-based studies using rat neonatal cardiomyocytes examined protein profiles in response to glucose (5.5-25 mM) and hydrogen peroxide (0-200 μM) concentrations over a range of time points. Protein expression profiles of control and STZ rat revealed changes to mitochondrial fusion and fission proteins; specifically Mfn1 and Mfn2 expression were increased compared to controls (p = 0.0140 and p = 0.0084, n = 4 respectively). Similarly, preliminary data from neonatal cardiomyocytes showed increases to Mfn2 expression after treatment with both high glucose and hydrogen peroxide. Electron microscopy images of the STZ myocardium revealed extensive rearrangement of the mitochondria.
Conclusion: These data suggest Mfn2 up-regulation is a feature of DCM. Future studies are focused upon understanding the functional consequences of elevated levels of Mfn2. Correlation of mitochondrial structure and function with Mfn2 levels will advance our understanding of the impact of diabetes upon the myocardium.
[1] de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 2008;456:605-10.
[2] Chen Y, Csordas G, Jowdy C, Schneider TG, Csordas N, Wang W, et al. Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca(2+) crosstalk. Circ Res. 2012;111:863-75.
[3] Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P. Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc Natl Acad Sci U S A. 2015.
Original languageEnglish
Number of pages2
Publication statusPublished - 2015
Event33rd Meeting of the ISHR-ES, July 1-4, 2015, Bordeaux, France - Bordeaux, France
Duration: 1 Jul 20154 Jul 2015
Conference number: 33


Conference33rd Meeting of the ISHR-ES, July 1-4, 2015, Bordeaux, France
Internet address


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