磷酸酶和张力蛋白同源物的上游开放阅读框可编

作者：王韵壹、李英、熊慧卿

本期文章：《细胞—代谢》：Volume 33 Issue 1

中山大学Nu Zhang课题组发现，磷酸酶和张力蛋白同源物的上游开放阅读框可编码乳酸代谢的断路器。2021年1月5日出版的《细胞—代谢》杂志发表了这一最新研究成果。

研究人员发现MP31可以充当一种分子“断路器”，这是一种由磷酸酶上游开放阅读框（uORF）和张力蛋白同源物（PTEN）编码的微肽，它通过与线粒体乳酸脱氢酶（mLDH）竞争烟酰胺腺嘌呤二核苷酸（NAD+）来限制线粒体中的乳酸-丙酮酸转化。敲除小鼠中的MP31同源物增强了整体乳酸的代谢，这表现为氧化磷酸化（OXPHOS）的加快，并增加了乳酸的消耗和产生。

小鼠星形胶质细胞中MP31同源物的条件敲除（cKO）启动了神经胶质瘤的形成，并缩短了动物的总体存活期，这些结果建立了MP31的肿瘤抑制作用。腹膜内注射的重组MP31能够穿透血脑屏障并抑制小鼠GBM异种移植而没有神经毒性，这表明了该微肽的临床意义和应用。这些发现揭示了胶质母细胞瘤中MP31调控乳酸代谢重编程的新模式。

据悉，从非翻译区产生的微肽的代谢作用目前仍然不清楚。

附：英文原文

Title: An Upstream Open Reading Frame in Phosphatase and Tensin Homolog Encodes a Circuit Breaker of Lactate Metabolism

Author: Nunu Huang, Fanying Li, Maolei Zhang, Huangkai Zhou, Zhipeng Chen, Xiaoyan Ma, Lixuan Yang, Xujia Wu, Jian Zhong, Feizhe Xiao, Xuesong Yang, Kun Zhao, Xixi Li, Xin Xia, Zexian Liu, Song Gao, Nu Zhang

Issue&Volume: 2021/01/05

Abstract: The metabolic role of micropeptides generated from untranslated regions remains unclear.Here we describe MP31, a micropeptide encoded by the upstream open reading frame (uORF)of phosphatase and tensin homolog (PTEN) acting as a “circuit breaker” that limitslactate-pyruvate conversion in mitochondria by competing with mitochondrial lactatedehydrogenase (mLDH) for nicotinamide adenine dinucleotide (NAD+). Knocking out the MP31 homolog in mice enhanced global lactate metabolism, manifestingas accelerated oxidative phosphorylation (OXPHOS) and increased lactate consumptionand production. Conditional knockout (cKO) of MP31 homolog in mouse astrocytes initiatedgliomagenesis and shortened the overall survival of the animals, establishing a tumor-suppressingrole for MP31. Recombinant MP31 administered intraperitoneally penetrated the blood-brainbarrier and inhibited mice GBM xenografts without neurological toxicity, suggestingthe clinical implication and application of this micropeptide. Our findings reveala novel mode of MP31-orchestrated lactate metabolism reprogramming in glioblastoma.

DOI: 10.1016/j.cmet.2020.12.008

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30663-X

期刊信息

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：22.415
官方网址：https://www.cell.com/cell-metabolism/home
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