{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNDUFA4L2, an atypical subunit of mitochondrial Complex I, is robustly induced under hypoxic conditions and overexpressed in multiple cancers. In clear cell renal cell carcinoma (ccRCC) and non‐small cell lung cancer, for example, loss of tumor suppressors and HIF‑1α stabilization drive high NDUFA4L2 expression that shifts cellular metabolism from oxidative phosphorylation toward glycolysis. This metabolic reprogramming reduces reactive oxygen species generation, supports mitochondrial dysfunction, and ultimately facilitates enhanced cell survival, chemoresistance, and angiogenesis. Similar protective effects under low‐oxygen conditions have been observed in cardiac stem cells, where NDUFA4L2 induction promotes viability in serum‑free hypoxia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in traditional tumor metabolism, NDUFA4L2 has diverse functions in other pathological settings. In pulmonary arterial hypertension, elevated NDUFA4L2 acts as a proliferative factor by enhancing ROS generation and activating downstream pathways such as p38‐5‑lipoxygenase, thereby contributing to vascular remodeling. In glioblastoma, increased expression of NDUFA4L2 correlates with enhanced proliferation and reduced apoptosis, partly through the induction of protective mitophagy and altered mitochondrial–lysosomal dynamics. Moreover, in the brain, NDUFA4L2 is constitutively expressed in mural cells—especially pericytes—where it couples mitochondrial oxygen consumption to the cellular hypoxic response, underscoring its key role in maintaining vascular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, NDUFA4L2 contributes to therapeutic resistance and metastatic progression in various tumors. In hepatocellular carcinoma, transcriptional upregulation of NDUFA4L2 by NFIB alleviates sorafenib‐induced ROS accumulation, thereby promoting drug resistance and facilitating tumor proliferation and invasion. In ccRCC, sustained NDUFA4L2 expression not only intensifies glycolytic flux but also promotes mitochondrial fragmentation and lysosomal reorganization—a constellation of effects that reinforces its role in metabolic reprogramming. In colon adenocarcinoma, overexpression of NDUFA4L2 is associated with epithelial–mesenchymal transition and aggressive cancer cell migration, suggesting its promise as a prognostic biomarker and therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Denise R Minton, Leiping Fu, Nigel P Mongan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2 in Clear Cell Renal Cell Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-15-1511"}], "href": "https://doi.org/10.1158/1078-0432.CCR-15-1511"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26783287"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26783287"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Robin Kit-Ho Lai, Iris Ming-Jing Xu, David Kung-Chun Chiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-15-1987"}], "href": "https://doi.org/10.1158/1078-0432.CCR-15-1987"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26819450"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26819450"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lei Liu, Gongbin Lan, Longkai Peng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NDUFA4L2 expression predicts poor prognosis in clear cell renal cell carcinoma patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ren Fail (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/0886022X.2016.1208517"}], "href": "https://doi.org/10.1080/0886022X.2016.1208517"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27453328"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27453328"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Juke Zheng, Minxue Zhang, Haixu Weng "}, {"type": "b", "children": [{"type": "t", "text": "Induction of the mitochondrial NDUFA4L2 protein by HIF-1a regulates heart regeneration by promoting the survival of cardiac stem cell."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2018.06.142"}], "href": "https://doi.org/10.1016/j.bbrc.2018.06.142"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29953852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29953852"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Giuseppe Lucarelli, Monica Rutigliano, Fabio Sallustio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrated multi-omics characterization reveals a distinctive metabolic signature and the role of NDUFA4L2 in promoting angiogenesis, chemoresistance, and mitochondrial dysfunction in clear cell renal cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Aging (Albany NY) (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/aging.101685"}], "href": "https://doi.org/10.18632/aging.101685"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30538212"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30538212"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Lifei Meng, Xuhui Yang, Xiao Xie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial NDUFA4L2 protein promotes the vitality of lung cancer cells by repressing oxidative stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Thorac Cancer (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/1759-7714.12984"}], "href": "https://doi.org/10.1111/1759-7714.12984"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30710412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30710412"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yun Liu, Xiaowei Nie, Jinquan Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NDUFA4L2 in smooth muscle promotes vascular remodeling in hypoxic pulmonary arterial hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.16193"}], "href": "https://doi.org/10.1111/jcmm.16193"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33340241"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33340241"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Zheng Chen, Xiangyu Wei, Xueyi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NDUFA4L2 promotes glioblastoma progression, is associated with poor survival, and can be effectively targeted by apatinib."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-021-03646-3"}], "href": "https://doi.org/10.1038/s41419-021-03646-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33828084"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33828084"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Claudia Mesa-Ciller, Guillermo Turiel, Andrea Guajardo-Grence, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cereb Blood Flow Metab (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/0271678X221118236"}], "href": "https://doi.org/10.1177/0271678X221118236"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35929074"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35929074"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Li Zhou, Lin-Hong Mao, Xia Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional regulation of NDUFA4L2 by NFIB induces sorafenib resistance by decreasing reactive oxygen species in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.15648"}], "href": "https://doi.org/10.1111/cas.15648"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36369883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36369883"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jaclyn M Kubala, Kristian B Laursen, Ryan Schreiner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NDUFA4L2 reduces mitochondrial respiration resulting in defective lysosomal trafficking in clear cell renal cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15384047.2023.2170669"}], "href": "https://doi.org/10.1080/15384047.2023.2170669"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36722045"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36722045"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Runlong Zhou, Zhe Sun, Ruijie Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pancancer analysis of NDUFA4L2 with focused role in tumor progression and metastasis of colon adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Oncol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12032-024-02531-1"}], "href": "https://doi.org/10.1007/s12032-024-02531-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39402288"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39402288"}]}]}]}