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 intraperitoneally 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.

从非翻译区产生的微肽的代谢作用尚不清楚。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 (uORF) 编码的微肽，充当“断路器”，通过与线粒体乳酸脱氢酶 (mLDH) 竞争来限制线粒体中的乳酸-丙酮酸转化烟酰胺腺嘌呤二核苷酸 (NAD ⁺）。在小鼠体内敲除 MP31 同源物可增强整体乳酸代谢，表现为加速氧化磷酸化 (OXPHOS) 和乳酸消耗和生产增加。小鼠星形胶质细胞中 MP31 同系物的条件性敲除 (cKO) 启动了胶质瘤生成并缩短了动物的总体存活时间，从而为 MP31 建立了肿瘤抑制作用。腹膜内施用的重组 MP31 可穿透血脑屏障并抑制小鼠 GBM 异种移植物而无神经毒性，表明该微肽的临床意义和应用。我们的研究结果揭示了胶质母细胞瘤中 MP31 协调乳酸代谢重编程的新模式。