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线粒体活性氧的产生受 ATP 酶抑制因子 1 控制，并调节认知。

Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition.

机构信息

Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.

出版信息

PLoS Biol. 2021 May 13;19(5):e3001252. doi: 10.1371/journal.pbio.3001252. eCollection 2021 May.

DOI:10.1371/journal.pbio.3001252
PMID:33983919
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8148373/
Abstract

The mitochondrial ATP synthase emerges as key hub of cellular functions controlling the production of ATP, cellular signaling, and fate. It is regulated by the ATPase inhibitory factor 1 (IF1), which is highly abundant in neurons. Herein, we ablated or overexpressed IF1 in mouse neurons to show that IF1 dose defines the fraction of active/inactive enzyme in vivo, thereby controlling mitochondrial function and the production of mitochondrial reactive oxygen species (mtROS). Transcriptomic, proteomic, and metabolomic analyses indicate that IF1 dose regulates mitochondrial metabolism, synaptic function, and cognition. Ablation of IF1 impairs memory, whereas synaptic transmission and learning are enhanced by IF1 overexpression. Mechanistically, quenching the IF1-mediated increase in mtROS production in mice overexpressing IF1 reduces the increased synaptic transmission and obliterates the learning advantage afforded by the higher IF1 content. Overall, IF1 plays a key role in neuronal function by regulating the fraction of ATP synthase responsible for mitohormetic mtROS signaling.

摘要

线粒体 ATP 合酶作为控制 ATP 产生、细胞信号转导和命运的细胞功能的关键枢纽出现。它受到 ATP 酶抑制因子 1（IF1）的调节，IF1 在神经元中高度丰富。在此，我们在小鼠神经元中敲除或过表达 IF1，以表明 IF1 剂量决定体内活性/无活性酶的比例，从而控制线粒体功能和线粒体活性氧物质（mtROS）的产生。转录组学、蛋白质组学和代谢组学分析表明，IF1 剂量调节线粒体代谢、突触功能和认知。IF1 的敲除会损害记忆，而过表达 IF1 则会增强突触传递和学习能力。从机制上讲，在过表达 IF1 的小鼠中抑制 IF1 介导的 mtROS 产生的增加会降低增强的突触传递，并消除由更高的 IF1 含量提供的学习优势。总的来说，IF1 通过调节负责mitohormetic mtROS 信号的 ATP 合酶的比例，在神经元功能中发挥关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/728e35731cba/pbio.3001252.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/6b9bc7934cfb/pbio.3001252.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/3a554dc1b1d0/pbio.3001252.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/b391b19d244f/pbio.3001252.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/6d4bd342a36c/pbio.3001252.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/192a49687ac8/pbio.3001252.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/9027e07c13d3/pbio.3001252.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/47dd1b4f5bd4/pbio.3001252.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/728e35731cba/pbio.3001252.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/6b9bc7934cfb/pbio.3001252.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/3a554dc1b1d0/pbio.3001252.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/b391b19d244f/pbio.3001252.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/6d4bd342a36c/pbio.3001252.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/192a49687ac8/pbio.3001252.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/9027e07c13d3/pbio.3001252.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/47dd1b4f5bd4/pbio.3001252.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2c5/8148373/728e35731cba/pbio.3001252.g008.jpg

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