Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death

Kyriakos Papanicolaou, Gladys A. Ngoh, Erinne R. Dabkowski, Kelly A. O'Connell, Rogerio F. Ribeiro, William C. Stanley, Kenneth Walsh

Research output: Contribution to journalArticle

Abstract

Molecular studies examining the impact of mitochondrial morphology on the mammalian heart have previously focused on dynamin related pro-tein-1 (Drp-1) and mitofusin-2 (Mfn-2), while the role of the other mitofusin isoform, Mfn-1, has remained largely unexplored. In the present study, we report the generation and initial characterization of cardiomyocyte-specific Mfn-1 knockout (Mfn-1 KO) mice. Using electron microscopic analysis, we detect a greater prevalence of small, spherical mitochondria in Mfn-1 KO hearts, indicating that the absence of Mfn-1 causes a profound shift in the mitochondrial fusion/ fission balance. Nevertheless, Mfn-1 KO mice exhibit normal left-ventricular function, and isolated Mfn-1 KO heart mitochondria display a normal respiratory repertoire. Mfn-1 KO myocytes are protected from mitochondrial depolarization and exhibit improved viability when challenged with reactive oxygen species (ROS) in the form of hydrogen peroxide (H 2O 2). Furthermore, in vitro studies detect a blunted response of KO mitochondria to undergo peroxide-induced mitochondrial permeability transition pore opening. These data suggest that Mfn-1 deletion confers protection against ROS-induced mitochondrial dysfunction. Collectively, we suggest that mitochondrial fragmentation in myocytes is not sufficient to induce heart dysfunction or trigger cardiomyocyte death. Additionally, our data suggest that endogenous levels of Mfn-1 can attenuate myocyte viability in the face of an imminent ROS overload, an effect that could be associated with the ability of Mfn-1 to remodel the outer mito-chondrial membrane.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume302
Issue number1
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

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Cardiac Myocytes
Muscle Cells
Reactive Oxygen Species
Cell Death
Knockout Mice
Mitochondria
Mitochondrial Dynamics
Dynamins
Heart Mitochondria
Peroxides
Left Ventricular Function
Hydrogen Peroxide
Protein Isoforms
Electrons
Membranes

Keywords

  • Apoptosis
  • Cardiomyocytes
  • Dynamin
  • GTPase
  • Membrane permeability
  • Mitochondrial dynamics
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. / Papanicolaou, Kyriakos; Ngoh, Gladys A.; Dabkowski, Erinne R.; O'Connell, Kelly A.; Ribeiro, Rogerio F.; Stanley, William C.; Walsh, Kenneth.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 302, No. 1, 01.01.2012.

Research output: Contribution to journalArticle

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