An Upstream Open Reading Frame in Phosphatase and Tensin Homolog Encodes a Circuit Breaker of Lactate Metabolism
An Upstream Open Reading Frame in Phosphatase and Tensin Homolog Encodes a Circuit Breaker of Lactate Metabolism
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磷酸酶和张力蛋白同源物中的上游开放阅读框编码乳酸代谢的断路器。
DOI：
10.1016/j.cmet.2020.12.008
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发表时间：
2021-01-05
期刊：
影响因子：
29
通讯作者：
Zhang, Nu
中科院分区：
文献类型：
--
作者：
Huang, Nunu;Li, Fanying;Zhang, Nu
从非翻译区产生的微肽的代谢作用仍然不清楚。在这里，我们描述了MP31，一种由磷酸酶和张力蛋白同源物（PTEN）的上游开放阅读框架（uORF）编码的微肽，其充当“断路器”，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（+））来限制线粒体中乳酸-丙酮酸转化。在小鼠中敲除MP31同源物增强了整体乳酸代谢，表现为加速的氧化磷酸化（OXPHOS）和增加的乳酸消耗和产生。小鼠星形胶质细胞中MP31同源物的条件性敲除（cKO）启动了胶质瘤的发生，缩短了动物的总生存期，确立了MP31的肿瘤抑制作用。腹腔注射重组MP31可穿透血脑屏障，抑制小鼠GBM移植瘤，且无神经毒性，提示该微肽的临床应用价值。我们的研究结果揭示了胶质母细胞瘤中MP31协调的乳酸代谢重编程的新模式。
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 limits lactate-pyruvate conversion in mitochondria by competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide adenine dinucleotide (NAD(+)). Knocking out the MP31 homolog in mice enhanced global lactate metabolism, manifesting as accelerated oxidative phosphorylation (OXPHOS) and increased lactate consumption and production. Conditional knockout (cKO) of MP31 homolog in mouse astrocytes initiated gliomagenesis and shortened the overall survival of the animals, establishing a tumor-suppressing role for MP31. Recombinant MP31 administered intra-peritoneally penetrated the blood-brain barrier and inhibited mice GBM xenografts without neurological toxicity, suggesting the clinical implication and application of this micropeptide. Our findings reveal a novel mode of MP31-orchestrated lactate metabolism reprogramming in glioblastoma.