Department of Neurosurgery, Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Cell Metab. 2021 Jan 5;33(1):128-144.e9. doi: 10.1016/j.cmet.2020.12.008.
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.
微肽是由非翻译区产生的，其代谢作用尚不清楚。本文描述了由磷酸酶和张力蛋白同源物（PTEN）上游开放阅读框（uORF）编码的微肽 MP31，其作为一种“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），限制线粒体中的乳酸-丙酮酸转化。在小鼠中敲除 MP31 同源物增强了整体的乳酸代谢，表现为氧化磷酸化（OXPHOS）加速和乳酸消耗和产生增加。条件敲除（cKO）小鼠星形胶质细胞中的 MP31 同源物会引发神经胶质瘤发生并缩短动物的总生存期，这确立了 MP31 的肿瘤抑制作用。腹腔内给予重组 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，提示该微肽具有临床意义和应用。我们的研究结果揭示了神经胶质瘤中 MP31 协调的乳酸代谢重编程的一种新方式。
