Decker Carl W, Garcia Jerome, Gatchalian Kristelle, Arceneaux Deronisha, Choi Clarice, Han Derick, Hernandez Jeniffer B
Keck Graduate Institute, Henry E. Riggs School of Applied Life Sciences, 535 Watson Drive, Claremont, CA, 91711, USA.
University of La Verne, Department of Biology, 1950 3rd Street, La Verne, CA, 91750, USA.
Biochem Biophys Rep. 2020 Oct 8;24:100824. doi: 10.1016/j.bbrep.2020.100824. eCollection 2020 Dec.
Mitochondria oscillate along a morphological continuum from fragmented individual units to hyperfused tubular networks. Their position at the junction of catabolic and anabolic metabolism couples this morphological plasticity, called mitochondrial dynamics, to larger cellular metabolic programs, which in turn implicate mitochondria in a number of disease states. In many cancers, fragmented mitochondria engage the cell with the biosynthetic capacity of aerobic glycolysis in service of proliferation and progression. Chemo-resistant cancers, however, favor remodeling dynamics that yield fused mitochondrial assemblies utilizing oxidative phosphorylation (OXPHOS) through the electron transport chain (ETC). In this study, expression of Mitofusin-2 (MFN-2), a GTPase protein mediator of mitochondrial fusion, was found to closely correlate to Jurkat leukemia cell survival post doxorubicin (DxR) assault. Moreover, this was accompanied by dramatically increased expression of OXPHOS respiratory complexes and ATP Synthase, as well as a commensurate escalation of state III respiration and respiratory control ratio (RCR). Importantly, CRISPR knockout of MFN-2 resulted in a considerable decrease of doxorubicin (DxR) median lethal dose compared to a treated wildtype control, suggesting an important role of mitochondrial fusion in chemotherapy sensitivity and acute resistance.
线粒体沿着从碎片化的单个单元到高度融合的管状网络的形态连续体振荡。它们在分解代谢和合成代谢的交界处的位置，将这种称为线粒体动力学的形态可塑性与更大的细胞代谢程序联系起来，这反过来又使线粒体与多种疾病状态相关。在许多癌症中，碎片化的线粒体利用有氧糖酵解的生物合成能力来促进细胞增殖和进展。然而，化疗耐药性癌症倾向于重塑动力学，通过电子传递链（ETC）利用氧化磷酸化（OXPHOS）产生融合的线粒体组件。在这项研究中，发现线粒体融合的GTPase蛋白介质Mitofusin-2（MFN-2）的表达与阿霉素（DxR）攻击后Jurkat白血病细胞的存活密切相关。此外，这伴随着OXPHOS呼吸复合体和ATP合酶的表达显著增加，以及状态III呼吸和呼吸控制率（RCR）的相应升高。重要的是，与处理过的野生型对照相比，CRISPR敲除MFN-2导致阿霉素（DxR）中位致死剂量显著降低，表明线粒体融合在化疗敏感性和急性耐药性中起重要作用。
