The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2121946119. doi: 10.1073/pnas.2121946119. Epub 2022 Mar 30.
Inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in various cellular functions including neuroprotection. Absence of IP6K2 causes impairment of oxidative phosphorylation regulated by creatine kinase-B. In the present study, we show that IP6K2 is involved in attenuation of PINK1-mediated mitochondrial autophagy (mitophagy) in the brain. Up-regulation of dynamin-related protein (Drp-1), as well as increased expression of mitochondrial biogenesis markers (PGC1-α and NRF-1) in the cerebella of IP6K2-deleted mice (IP6K2-knockout), point to the involvement of IP6K2 in the regulation of mitochondrial fission. Knockdown of IP6K2 also leads to augmented glycolysis, potentially as a compensatory mechanism for decreased mitochondrial respiration. Overexpressing IP6K2 as well as IP6K2-kinase dead mutant in IP6K2-knockdown N2A cells reverses the expression of mitophagy markers, demonstrating that IP6K2-induced mitoprotection is catalytically/kinase independent. IP6K2 supplementation in K2-PINK1 double-knockdown N2A cells fails to reverse the expression of the mitophagic marker, LC3-II, indicating that the mitoprotective effect of IP6K2 is dependent on PINK1. Overall, our study reveals a key neuroprotective role of IP6K2 in the prevention of PINK1-mediated mitophagy in the brain.
肌醇六磷酸激酶（IP6K）家族能够生成肌醇五磷酸（IP7）等焦磷酸肌醇，其中 IP6K2 参与多种细胞功能，包括神经保护。IP6K2 的缺失会导致肌酸激酶-B 调控的氧化磷酸化受损。本研究表明，IP6K2 参与了脑内 PINK1 介导的线粒体自噬（mitophagy）的衰减。IP6K2 缺失小鼠（IP6K2 敲除）小脑中动力相关蛋白（Drp-1）上调，以及线粒体生物发生标志物（PGC1-α 和 NRF-1）的表达增加，表明 IP6K2 参与了线粒体分裂的调节。IP6K2 的敲低也会导致糖酵解增加，可能是线粒体呼吸减少的代偿机制。在 IP6K2 敲低的 N2A 细胞中过表达 IP6K2 以及无激酶活性的 IP6K2 突变体，会逆转 mitophagy 标志物的表达，表明 IP6K2 诱导的线粒体保护作用不依赖于酶活性/激酶活性。在 K2-PINK1 双敲低的 N2A 细胞中补充 IP6K2 并不能逆转 mitophagic 标志物 LC3-II 的表达，表明 IP6K2 的保护作用依赖于 PINK1。总的来说，我们的研究揭示了 IP6K2 在预防脑内 PINK1 介导的 mitophagy 中的关键神经保护作用。
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