Xiong Guohang, Yun Fang, Jiang Lu, Yi Zihan, Yi Xiaojia, Yang Lijuan, Zhang Xuedan, Li Xiaoyu, Yang Zhe, Zhang Qiao, Sai Buqing, Kuang Yingmin, Zhu Yuechun
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, 650500, China.
Research Center for Clinical Medicine, First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, 650032, China.
Cell Death Differ. 2025 May 22. doi: 10.1038/s41418-025-01525-4.
NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) is the core subunit of the respiratory chain complex I (CI). We found NDUFS3 were abnormally elevated in human melanoma and promoted melanoma proliferation. Furthermore, NDUFS3 could promote the oxidative phosphorylation (OXPHOS) and the pentose phosphate pathway (PPP), as well as attenuated glycolysis. As NDUFS3-mediated the metabolic changes of OXPHOS and glucose metabolism, melanoma cells produced more ATP, resulting in the inhibition of AMP kinase (AMPK). AMPK induced phosphoribosyl pyrophosphate synthetase1 (PRPS1) phosphorylation, which resulted in suppressed PRPS1 activity. Briefly, the NDUFS3-AMPK-PRPS1 signaling axis coupled OXPHOS, glucose metabolism, and purine nucleotide biosynthesis to regulate melanoma proliferation. Our study highlighted an unrecognized role for NDUFS3 in melanoma, which might be used as a potential therapeutic target for the treatment of this type of cancer. NDUFS3 regulating PRPS1 activity through AMPK to affect melanoma proliferation.
NADH脱氢酶[泛醌]铁硫蛋白3（NDUFS3）是呼吸链复合体I（CI）的核心亚基。我们发现NDUFS3在人类黑色素瘤中异常升高，并促进黑色素瘤增殖。此外，NDUFS3可促进氧化磷酸化（OXPHOS）和磷酸戊糖途径（PPP），并减弱糖酵解。由于NDUFS3介导了OXPHOS和葡萄糖代谢的变化，黑色素瘤细胞产生了更多的三磷酸腺苷（ATP），导致腺苷酸激酶（AMPK）受到抑制。AMPK诱导磷酸核糖焦磷酸合成酶1（PRPS1）磷酸化，从而导致PRPS1活性受到抑制。简而言之，NDUFS3-AMPK-PRPS1信号轴将OXPHOS、葡萄糖代谢和嘌呤核苷酸生物合成联系起来，以调节黑色素瘤增殖。我们的研究突出了NDUFS3在黑色素瘤中未被认识的作用，其可能作为治疗这类癌症的潜在治疗靶点。NDUFS3通过AMPK调节PRPS1活性以影响黑色素瘤增殖。
