bims-miptne 2025-01-26 papers

bioRxiv. 2025 Jan 09. pii: 2025.01.08.631936. [Epub ahead of print]

Impaired oxidative phosphorylation drives primary tumor escape and metastasis.

Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.

DOI: https://doi.org/10.1101/2025.01.08.631936

Front Genet. 2024 ;15 1515045

Exploring the prognostic significance of lactate-mitochondria-related genes in prostate cancer.

Yuan Wang, Ronghui Chen, Feng-Le Jiang, Xin Jiang, Yuehong Zhou, Yingying Zhou, Xinyi Hong, Chaoying Lin, Wei-Jia Wang, Sufang Qiu.

Prostate cancer (PCa) is a common and serious health issue among older men globally. Metabolic reprogramming, particularly involving lactate and mitochondria, plays a key role in PCa progression, but studies linking these factors to prognosis are limited. To identify novel prognostic markers of PCa based on lactate-mitochondria-related genes (LMRGs), RNA sequencing data and clinical information of PCa from The Cancer Genome Atlas (TCGA) and the cBioPortal database were used to construct a lactate-mitochondria-related risk signature. Here, we established a novel nine-LMRG risk signature for PCa, and Kaplan-Meier curves confirmed a worse prognosis for high-risk subgroups in the TCGA dataset. Meanwhile, a nomogram that effectively predicts the prognosis of PCa patients was also constructed. Next, close associations between the lactate-mitochondria-related signature and the immune microenvironment were examined to clarify the role of LMRGs in shaping the immune landscape. Furthermore, as the only lactate-related gene among the nine key prognostic risk genes, myeloperoxidase (MPO) was identified as a key factor that mediates lactate production in vitro and in vivo through attenuation of the glycolytic pathway. More importantly, MPO significantly inhibited PCa cell migration, invasion, and epithelial-mesenchymal transition (EMT), indicating its potential as an anticancer gene. Additionally, PCa with high MPO expression is highly sensitive to chemotherapeutic agents and mitochondrial inhibitors, highlighting its potential as an improved therapeutic strategy for PCa management.

Keywords: drug sensitivity; lactate-mitochondria-related genes (LMRGs); metastasis; myeloperoxidase (MPO); prognosis; prostate cancer (PCa)

DOI: https://doi.org/10.3389/fgene.2024.1515045

FEBS J. 2025 Jan 19.

LDHAα, a lactate dehydrogenase A isoform, promotes glycolysis and tumor progression.

Bingqing Huang, Wencui Shen, Yujiao Jia, Li Qin, Haoxu Wang, Qi Sun, Zhijian Xiao, Rongxin Zhang, Huijun Wang.

Lactate dehydrogenase A (LDHA) is upregulated in multiple cancer types and contributes to the Warburg effect. Several studies have found that many tumor-related genes have subtypes and play important roles in promoting cancer development. Here, we identified a novel LDHA transcript, which produced a new protein 3 kDa larger than LDHA, which we named LDHAα. We found that multiple cancer cell lines express LDHAα, and ectopic expression of LDHAα led to a higher proliferation and migration rate in vitro. Ectopic expression of LDHAα could also promote tumor cell growth in vivo. Conversely, deletion of LDHAα by CRISPR-sgRNA significantly inhibited the growth of tumor cells. LDHAα was found to be mainly located in the cytoplasm, and overexpression or deletion of LDHAα could significantly affect the glucose uptake and lactate production of tumor cells. Further investigation showed that c-MYC and FOXM1 could markedly modulate the expression of both LDHA and LDHAα, especially c-MYC. We found that a small molecular compound targeting LDHA could also inhibit the enzyme activity of LDHAα. LDHAα, LDHA and c-MYC expression was significantly higher in human acute lymphocytic leukemia and colorectal cancer tissue specimens compared to normal controls. In conclusion, our study identified LDHAα as a subtype of LDHA and highlighted its critical role in tumor metabolism, providing a potential new therapeutic target for tumor diagnosis and treatment.

Keywords: glycolysis; isoform; lactate dehydrogenase A; metabolism; tumor

DOI: https://doi.org/10.1111/febs.17374

Biochim Biophys Acta Bioenerg. 2025 Jan 17. pii: S0005-2728(25)00006-4. [Epub ahead of print] 149540

Purification and characterization of recombinant human mitochondrial proton-pumping nicotinamide nucleotide transhydrogenase.

Sangjin Hong, Simone Graf, Christoph von Ballmoos, Robert B Gennis.

The human mitochondrial nicotinamide nucleotide transhydrogenase (NNT) uses the proton motive force to drive hydride transfer from NADH to NADP+ and is a major contributor to the generation of mitochondrial NADPH. NNT plays a critical role in maintaining cellular redox balance. NNT-deficiency results in oxidative damage and its absence results in familial glucocorticoid deficiency. Recently it has also become clear that NNT is a tumor promoter whose presence in mouse models of non-small cell lung cancer results in enhanced tumor growth and aggressiveness. The presence of NNT mitigates the effects of oxidative stress and facilitates cancer cell proliferation, suggesting NNT-inhibition as a promising therapeutic strategy. The human NNT is a homodimer in which each subunit has a molecular weight of 114 kDa and 14 transmembrane spans. Here we report on the development of a system for isolating full-length recombinant human NNT using Escherichia coli. The purified enzyme is catalytically active, and the enzyme reconstituted into proteoliposomes pumps protons and generates a proton motive force capable of driving ATP synthesis by E. coli ATP synthase. The recombinant human NNT will facilitate structural and biochemical studies as well as provide a useful tool to develop and characterize potential anti-cancer therapeutics.

Keywords: Cancer; Familial glucocorticoid deficiency; Heterologous overexpression; Human nicotinamide nucleotide transhydrogenase; Integral membrane protein

DOI: https://doi.org/10.1016/j.bbabio.2025.149540