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

Abstract

deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol 302: H167-H179, 2012. First published October 28, 2011 doi:10.1152/ajpheart.00833.2011.-Molecular studies examining the impact of mitochondrial morphology on the mammalian heart have previously focused on dynamin related protein-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 leftventricular 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 (H2O2). Furthermore, in vitro studies detect a blunted response of KO mitochondria to undergo peroxideinduced mitochondrial permeability transition pore opening. These data suggest that Mfn-1 deletion confers protection against ROSinduced 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 mitochondrial membrane.

Central Role of Mitofusin 2 in Autophagosome-Lysosome Fusion in Cardiomyocytes

“…Consistent with this, a recent study reported that combined ablation of MFN1/ MFN2 in adult mouse heart results in fragmented mitochondria and decreased mitochondrial function, suggesting that mitochondrial fusion is essential for cardiac function (25). In contrast, cardiac MFN1 knock-out mice have normal cardiac function, although with smaller mitochondria; moreover, MFN1-deficient cardiomyocytes show improved viability in response to reactive oxygen species challenge (54). A recent study by Papanicolaou et al (26) reported that MFN2 depletion in the heart leads to modest myocyte hypertrophy, mild left ventricular dysfunction, and enlarged subsarcolemmal mitochondria with a lower mitochondrial membrane potential but normal respiration.…”

Mfn2 is critical for brown adipose tissue thermogenic function

“…Mfn1 is an essential protein for mitochondria fusion events. Accordingly, decreased Mfn1 function has been shown to trigger a profound shift in the fusion/fission balance, toward a dramatically fragmented mitochondrial network in most, if not all, cells and tissues tested to date (Chen et al , 2003; Park et al , 2008; Papanicolaou et al , 2012; Dietrich et al , 2013; Kulkarni et al , 2016). Further, While Mfn1 mRNA levels did not compensate for Mfn2 loss, we observed that Mfn1 protein slightly decreased in the BAT and WAT form Mfn2‐adKO mice (Fig EV1A).…”

Chronic stress induces ageing-associated degeneration in rat Leydig cells

“…The sections were double stained with saturated 3% (w/v) uranyl acetate in 50% (v/v) alcohol and lead citrate; slides were then observed using a transmission electron microscope (Philips CM120, Eindhoven, The Netherlands). 22 Isolation and purification of Leydig cells Rats were anaesthetized using CO 2 and sacrificed by decapitation, and the testes were removed. The procedure for Leydig cell isolation was previously described.…”