Programa de Fisiopatología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile.
Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile.
Biochim Biophys Acta Mol Basis Dis. 2020 May 1;1866(5):165659. doi: 10.1016/j.bbadis.2019.165659. Epub 2019 Dec 28.
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.
心肌细胞的丢失是缺血再灌注 (IR) 损伤后心肌功能障碍的主要原因。线粒体功能障碍和改变的线粒体网络动力学在心肌细胞死亡中起核心作用。蛋白酶体抑制在 IR 情况下具有心脏保护作用；然而，这种保护的机制尚不清楚。几种调节线粒体动力学和能量代谢的蛋白质，包括线粒体融合蛋白 2 (Mfn2)，可被蛋白酶体降解。本研究旨在评估蛋白酶体抑制是否可以通过维持 Mfn2 水平和保持线粒体网络完整性来保护心肌细胞免受 IR 损伤。使用离体 Langendorff 灌注大鼠心脏和体外新生大鼠心室肌细胞，我们表明蛋白酶体抑制剂 MG132 可减少 IR 诱导的心肌细胞死亡。此外，MG132 可维持线粒体质量，防止线粒体网络碎片化，并消除 IR 诱导的心脏组织和培养的心肌细胞中 Mfn2 水平的降低。有趣的是，Mfn2 的过表达也可防止心肌细胞死亡。这种作用显然是 Mfn2 特异性的，因为另一种涉及线粒体动力学的蛋白质 Miro1 的过表达不能赋予相同的保护作用。我们的结果表明，蛋白酶体抑制可保护心肌细胞免受 IR 损伤。这种作用可能部分是通过维持 Mfn2 从而维持线粒体完整性介导的。
