Inhibition of the proteasome preserves Mitofusin-2 and mitochondrial integrity, protecting cardiomyocytes during ischemia-reperfusion injury

Ivonne Olmedo, Gonzalo Pino, Jaime A. Riquelme, Pablo Aranguiz, Magda C. Díaz, Camila López-Crisosto, Sergio Lavandero, Paulina Donoso, Zully Pedrozo, Gina Sánchez

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Abstract

Cardiomyocyte loss is the main cause of myocardial dysfunction following an ischemia-reperfusion (IR) injury. Mitochondrial dysfunction and altered mitochondrial network dynamics play central roles in cardiomyocyte death. Proteasome inhibition is cardioprotective in the setting of IR; however, the mechanisms underlying this protection are not well-understood. Several proteins that regulate mitochondrial dynamics and energy metabolism, including Mitofusin-2 (Mfn2), are degraded by the proteasome. The aim of this study was to evaluate whether proteasome inhibition can protect cardiomyocytes from IR damage by maintaining Mfn2 levels and preserving mitochondrial network integrity. Using ex vivo Langendorff-perfused rat hearts and in vitro neonatal rat ventricular myocytes, we showed that the proteasome inhibitor MG132 reduced IR-induced cardiomyocyte death. Moreover, MG132 preserved mitochondrial mass, prevented mitochondrial network fragmentation, and abolished IR-induced reductions in Mfn2 levels in heart tissue and cultured cardiomyocytes. Interestingly, Mfn2 overexpression also prevented cardiomyocyte death. This effect was apparently specific to Mfn2, as overexpression of Miro1, another protein implicated in mitochondrial dynamics, did not confer the same protection. Our results suggest that proteasome inhibition protects cardiomyocytes from IR damage. This effect could be partly mediated by preservation of Mfn2 and therefore mitochondrial integrity.

Original languageEnglish
Article number165659
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1866
Issue number5
DOIs
Publication statusPublished - 1 May 2020

Keywords

  • Ischemia/reperfusion
  • Mitochondria
  • Mitofusin-2
  • Proteasome

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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  • Cite this

    Olmedo, I., Pino, G., Riquelme, J. A., Aranguiz, P., Díaz, M. C., López-Crisosto, C., Lavandero, S., Donoso, P., Pedrozo, Z., & Sánchez, G. (2020). Inhibition of the proteasome preserves Mitofusin-2 and mitochondrial integrity, protecting cardiomyocytes during ischemia-reperfusion injury. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1866(5), [165659]. https://doi.org/10.1016/j.bbadis.2019.165659