The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Proc Natl Acad Sci U S A. 2021 Feb 9;118(6). doi: 10.1073/pnas.2020695118.
Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. IP6Ks convert IP6 to pyrophosphates such as diphosphoinositol pentakisphosphate (IP7) and bis-diphosphoinositol tetrakisphosphate (IP8). IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. The inositol hexakisphosphate kinase 2 (IP6K2) controls cellular apoptosis. To explore roles for IP6K2 in brain function, we elucidated its protein interactome in mouse brain revealing a robust association of IP6K2 with creatine kinase-B (CK-B), a key enzyme in energy homeostasis. Cerebella of IP6K2-deleted mice (IP6K2-knockout [KO]) produced less phosphocreatine and ATP and generated higher levels of reactive oxygen species and protein oxidative damage. In IP6K2-KO mice, mitochondrial dysfunction was associated with impaired expression of the cytochrome-c1 subunit of complex III of the electron transport chain. We reversed some of these effects by combined treatment with -acetylcysteine and phosphocreatine. These findings establish a role for IP6K2-CK-B interaction in energy homeostasis associated with neuroprotection.
肌醇六磷酸激酶（IP6Ks）调节各种生物过程。IP6Ks 将 IP6 转化为焦磷酸盐，如二磷酸肌醇 pentakisphosphate（IP7）和双二磷酸肌醇 tetrakisphosphate（IP8）。哺乳动物中的 IP7 是由肌醇六磷酸激酶家族的成员 IP6K1、IP6K2 和 IP6K3 产生的，它们具有不同的生物学功能。肌醇六磷酸激酶 2（IP6K2）控制细胞凋亡。为了探索 IP6K2 在大脑功能中的作用，我们阐明了其在小鼠大脑中的蛋白质相互作用组，发现 IP6K2 与肌酸激酶-B（CK-B）强烈相关，CK-B 是能量稳态的关键酶。IP6K2 缺失小鼠（IP6K2 敲除 [KO]）的小脑产生的磷酸肌酸和 ATP 较少，产生的活性氧和蛋白质氧化损伤水平较高。在 IP6K2-KO 小鼠中，线粒体功能障碍与电子传递链复合体 III 的细胞色素 c1 亚基表达受损有关。我们通过联合使用 -乙酰半胱氨酸和磷酸肌酸治疗部分逆转了这些影响。这些发现确立了 IP6K2-CK-B 相互作用在与神经保护相关的能量稳态中的作用。
