Da Costa Renata T, Nichenko Anna, Perez Matheus M, Tokarska-Schlattner Malgorzata, Kavehmoghaddam Sheida, Hambardikar Vedangi, Scoma Ernest R, Seifert Erin L, Schlattner Uwe, Drake Joshua C, Solesio Maria E
Department of Biology, and Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USA.
Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
Mol Metab. 2025 Jan;91:102077. doi: 10.1016/j.molmet.2024.102077. Epub 2024 Nov 30.
Inorganic polyphosphate (polyP) is an evolutionary and ancient polymer composed by orthophosphate units linked by phosphoanhydride bonds. In mammalian cells, polyP shows a high localization in mammalian mitochondria, and its regulatory role in various aspects of bioenergetics has already been demonstrated, via molecular mechanism(s) yet to be fully elucidated. In recent years, a role for polyP in signal transduction, from brain physiology to the bloodstream, has also emerged.
In this manuscript, we explored the intriguing possibility that the effects of polyP on signal transduction could be mechanistically linked to those exerted on bioenergetics.
To conduct our studies, we used a combination of cellular and animal models.
Our findings demonstrate for the first time the intimate crosstalk between the levels of polyP and the activation status of the AMPK signaling pathway, via a mechanism involving free phosphate homeostasis. AMPK is a key player in mammalian cell signaling, and a crucial regulator of cellular and mitochondrial homeostasis. Our results show that the depletion of mitochondrial polyP in mammalian cells downregulates the activity of AMPK. Moreover, increased levels of polyP activate AMPK. Accordingly, the genetic downregulation of AMPKF0611 impairs polyP levels in both SH-SY5Y cells and in the brains of female mice.
This manuscript sheds new light on the regulation of AMPK and positions polyP as a potent regulator of mammalian cell physiology beyond mere bioenergetics, paving the road for using its metabolism as an innovative pharmacological target in pathologies characterized by dysregulated bioenergetics.
无机多聚磷酸盐（polyP）是一种进化上古老的聚合物，由通过磷酸酐键连接的正磷酸盐单元组成。在哺乳动物细胞中，polyP在哺乳动物线粒体中高度定位，并且其在生物能量学各个方面的调节作用已经通过尚未完全阐明的分子机制得到证实。近年来，polyP在从脑生理学到血液循环的信号转导中的作用也已显现。
在本手稿中，我们探讨了一种有趣的可能性，即polyP对信号转导的影响可能在机制上与对生物能量学的影响相关联。
为了进行我们的研究，我们使用了细胞和动物模型的组合。
我们的研究结果首次证明了polyP水平与AMPK信号通路激活状态之间存在密切的相互作用，其机制涉及游离磷酸盐稳态。AMPK是哺乳动物细胞信号转导中的关键参与者，也是细胞和线粒体稳态的关键调节因子。我们的结果表明，哺乳动物细胞中线粒体polyP的消耗会下调AMPK的活性。此外，polyP水平的增加会激活AMPK。因此，AMPKF0611的基因下调会损害SH-SY5Y细胞和雌性小鼠大脑中的polyP水平。
本手稿为AMPK的调节提供了新的见解，并将polyP定位为哺乳动物细胞生理学的有效调节因子，而不仅仅是生物能量学方面，为将其代谢作为生物能量学失调相关疾病的创新药理学靶点铺平了道路。
