Le He, Jianghua Lin, Shaojuan Lu, Hao Li, Jie Chen, Xinyi Wu, Qixin Yan, Hailiang Liu, Hui Li, Yufeng Shi
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引用次数: 0
Abstract
Creatine kinases are essential for maintaining cellular energy balance by facilitating the reversible transfer of a phosphoryl group from ATP to creatine, however, their role in mitochondrial ATP production remains unknown. This study shows creatine kinases, including CKMT1A, CKMT1B, and CKB, are highly expressed in cells relying on the mitochondrial F1F0 ATP synthase for survival. Interestingly, silencing CKB, but not CKMT1A or CKMT1B, leads to a loss of sensitivity to the inhibition of F1F0 ATP synthase in these cells. Mechanistically, CKB promotes mitochondrial ATP but reduces glycolytic ATP production by suppressing mitochondrial calcium (mCa2+) levels, thereby preventing the activation of mitochondrial permeability transition pore (mPTP) and ensuring efficient mitochondrial ATP generation. Further, CKB achieves this regulation by suppressing mCa2+ levels through the inhibition of AKT activity. Notably, the CKB-AKT signaling axis boosts mitochondrial ATP production in cancer cells growing in a mouse tumor model. Moreover, this study also uncovers a decline in CKB expression in peripheral blood mononuclear cells with aging, accompanied by an increase in AKT signaling in these cells. These findings thus shed light on a novel signaling pathway involving CKB that directly regulates mitochondrial ATP production, potentially playing a role in both pathological and physiological conditions.
肌酸激酶能促进磷酸基团从 ATP 向肌酸的可逆转移,对维持细胞能量平衡至关重要,但它们在线粒体 ATP 生产中的作用仍不清楚。本研究表明,肌酸激酶(包括 CKMT1A、CKMT1B 和 CKB)在依赖线粒体 F1F0 ATP 合成酶生存的细胞中高度表达。有趣的是,沉默 CKB 而不是 CKMT1A 或 CKMT1B 会导致这些细胞对抑制 F1F0 ATP 合成酶失去敏感性。从机理上讲,CKB 通过抑制线粒体钙(mCa2+)水平,促进线粒体 ATP 的生成,但减少糖酵解 ATP 的生成,从而阻止线粒体通透性转换孔(mPTP)的活化,确保线粒体 ATP 的高效生成。此外,CKB 通过抑制 AKT 的活性来抑制 mCa2+ 水平,从而实现这种调节。值得注意的是,CKB-AKT 信号轴促进了在小鼠肿瘤模型中生长的癌细胞线粒体 ATP 的生成。此外,这项研究还发现,随着年龄的增长,外周血单核细胞中的 CKB 表达下降,同时这些细胞中的 AKT 信号转导增加。因此,这些发现揭示了一种涉及 CKB 的新型信号通路,该通路直接调节线粒体 ATP 的产生,可能在病理和生理条件下发挥作用。
期刊介绍:
Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.