Mitofusin-2 Maintains Mitochondrial Structure and Contributes to Stress-Induced Permeability Transition in Cardiac Myocytes

Abstract

Mitofusin-2 (Mfn-2) is a dynamin-like protein that is involved in the rearrangement of the outer mitochondrial membrane. Research using various experimental systems has shown that Mfn-2 is a mediator of mitochondrial fusion, an evolutionarily conserved process responsible for the surveillance of mitochondrial homeostasis. Here, we find that cardiac myocyte mitochondria lacking Mfn-2 are pleiomorphic and have the propensity to become enlarged. Consistent with an underlying mild mitochondrial dysfunction, Mfn-2-deficient mice display modest cardiac hypertrophy accompanied by slight functional deterioration. The absence of Mfn-2 is associated with a marked delay in mitochondrial permeability transition downstream of Ca 2؉ stimulation or due to local generation of reactive oxygen species (ROS). Consequently, Mfn-2-deficient adult cardiomyocytes are protected from a number of cell death-inducing stimuli and Mfn-2 knockout hearts display better recovery following reperfusion injury. We conclude that in cardiac myocytes, Mfn-2 controls mitochondrial morphogenesis and serves to predispose cells to mitochondrial permeability transition and to trigger cell death.

Role of mitofusin 2 in the protective effect of breviscapine against hepatic ischemia/reperfusion injury in rats

“…As mentioned above, mPTP opening leads to cytochrome c release from the mitochondria to the cytosol. It has been reported that upregulating the expression of Mfn2 may reduce the release of cytochrome c (26), while downregulating the expression of Mfn2 exacerbates ceramide-induced mitochondrial dysfunction and release of cytochrome c (27). These findings indicate that Mfn2 reduces apoptosis through inhibiting the mitochondrial apoptosis pathway.…”

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

“…Similar studies have reported the effective use of siRNAs to knockdown both Nox and Mfn2 and inhibit ROS production and apoptosis in cardiac cells, including HL‐1 cardiomyocytes (Yeh et al, 2011), H9c2 cardiomyocytes, (Shen et al, 2007), cultured neonatal rat cardiomyocytes (Papanicolaou et al, 2011) and mouse ventricular cells (Moe et al, 2011). However, while this investigation found no changes in apoptosis in DOX‐treated HL‐1 cardiomyocytes in the presence of Nox2 or Mfn2 knockdown, it is possible that efficacy of transfection may have influenced the measured endpoint.…”

“…Additionally, siRNA inhibition of Mfn2 prevented oxidative stress‐induced apoptotic cell death in H9c2 cardiomyocytes (Karbowski et al, 2002). Strikingly, Mfn2 is reported to protect the heart against ischaemia–reperfusion injury and ROS‐mediated damage (Papanicolaou et al, 2011). It was therefore concluded that Mfn2 not only serves to maintain mitochondrial morphology in cardiomyocytes but also promotes mitochondrial permeability transition activation in response to Ca 2+ stimulation or ROS generation, predisposing the cells to a number of cell‐death‐inducing stimuli.…”

“…However, while this investigation found no changes in apoptosis in DOX‐treated HL‐1 cardiomyocytes in the presence of Nox2 or Mfn2 knockdown, it is possible that efficacy of transfection may have influenced the measured endpoint. Indeed, highly oxidative tissues such as the heart require constant energy production, and as mitochondria are the powerhouse of the cardiomyocyte comprising a large proportion of cytoplasmic volume, it is possible that there is such a high level of Mfn2 expression in HL‐1 cardiomyocytes that the observed effects of Mfn2 siRNA on cell apoptosis may have underestimated the involvement of Mfn2 (Bach et al, 2003; Papanicolaou et al, 2011). Indeed, when a higher level of knockdown was achieved, a lack of Mfn2 corresponded with reduction of caspase 3/7 activity, assessed by both DEVD and PARP‐1 cleavage.…”

“…As further information emerges, it seems that there is equivalent evidence that maintained levels of Mfn2 may be required to counteract cell oxidative stress; for example, further to ROS induced by hypoxia/reoxygenation in cardiomyocytes, up‐regulated Mfn2 expression prevented imbalance in mitochondrial dynamics (Dong et al, 2016). Loss of Mfn2 also delayed membrane depolarization in isolated cardiomyocytes from adult Mfn2 −/− mice, leading to the suggestion that Mfn2 may function to control mitochondrial permeability transition pore opening (Papanicolaou et al, 2011). Similarly, cardiac‐specific deletion of Mfn2 produced dissipation of mitochondrial membrane potential and elevated ROS production (Chen et al, 2012), whilst overexpression of Mfn2 was found to increase the percentage of cells containing elongated mitochondria, thereby reducing mitochondrial permeability transition pore opening and cell death after simulated ischaemia/reperfusion injury (Ong et al, 2010).…”