Elucidating the Nexus of Mitochondrial Dysfunction and Oncometabolite Accumulation in Tumorigenesis
Main Article Content
Keywords
Cancer, Mitochondrial Dysfunction, Oncometabolites, Warburg Effect, Metabolic Reprogramming, Cachexia, Aurora kinase A, glioblastoma
Abstract
Cancer is a complex disease driven by disruptions in cellular metabolism and mitochondrial function, enabling malignant cells to proliferate unchecked, evade apoptosis, and metastasize to distant organs. This exhaustive review elucidates the metabolic dysregulations inherent to cancer, with a particular focus on mitochondrial dysfunction, the accumulation of oncometabolites, and the reprogramming of metabolic pathways. A comprehensive literature search was conducted across major scientific databases, including PubMed, Web of Science, Scopus, and ScienceDirect, spanning January 2010 to March 2025. Controlled vocabulary and Boolean operators were employed to capture relevant studies, focusing on cancer metabolism, metabolic reprogramming, tumour markers, oncometabolites, mitochondrial dysfunction, and regulatory pathways. Extracted data were organized into thematic areas, and a qualitative synthesis approach was used to integrate findings, identifying common mechanistic patterns underlying tumour initiation, progression, and metastasis. The Warburg effect, a typical feature of cancer metabolism, is characterized by a predilection for aerobic glycolysis, thereby supporting biosynthetic processes and contributing to tumour microenvironment acidification and immune suppression. Mitochondrial dysfunction triggers genomic instability and oncogenic transformation. Meanwhile, oncometabolites like 2-hydroxyglutarate, fumarate, and sarcosine disrupt cellular signalling and epigenetic regulation, promoting tumour growth and progression. The clinical significance of tumour markers and metabolic biomarkers is underscored, and the systemic metabolic sequelae of cancer, including cancer-associated cachexia, are expounded upon. In glioblastoma, Aurora kinase A inhibition reverses the Warburg effect, decreasing glucose uptake and boosting oxidative phosphorylation. Cancer-associated fibroblasts exhibit aerobic glycolysis, promoting tumor growth and metastasis via the reverse Warburg effect. Glycolysis inhibition suppresses tumor growth in pancreatic cancer, and the Warburg effect contributes to chemoresistance by upregulating glycolytic enzymes and increasing lactate production. Targeting the Warburg effect, including inhibiting glycolytic enzymes and modulating mitochondrial function, offers potential therapeutic strategies for cancer treatment. This review provides a comprehensive exposition of the biochemical mechanisms underpinning metabolic derangements in cancer, which may unveil novel avenues for diagnostic and therapeutic interventions.
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Bragazzi NL, Sellami M. Cancer bioenergetics as emerging holistic cancer theory: The role of metabolic fluxes and transport proteins involved in metabolic pathways in the pathogenesis of malignancies. State-of-the-art and future prospects. Advances in Protein Chemistry and Structural Biology. 2021 Jan 1;123:27-47.
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Cassim S, Vučetić M, Ždralević M, Pouyssegur J. Warburg and beyond: the power of mitochondrial metabolism to collaborate or replace fermentative glycolysis in cancer. Cancers. 2020 Apr 30;12(5):1119.
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Schwartz L, T Supuran C, O Alfarouk K. The Warburg effect and the hallmarks of cancer. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). 2017 Feb 1;17(2):164-70.
Jiang M, Fang H, Tian H. Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer. Theranostics. 2025 Jan 1;15(1):155.
Scatena R. Mitochondria and cancer: a growing role in apoptosis, cancer cell metabolism and dedifferentiation. Advances in Mitochondrial Medicine. 2011 Dec 22:287-308.
Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, Zhang B, Meng Q, Yu X, Shi S. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Molecular cancer. 2021 Oct 11;20(1):131.
Nguyen TT, Shang E, Shu C, Kim S, Mela A, Humala N, Mahajan A, Yang HW, Akman HO, Quinzii CM, Zhang G. Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma. Nature Communications. 2021 Sep 1;12(1):5203.
Nguyen TT, Shang E, Shu C, Kim S, Mela A, Humala N, Mahajan A, Yang HW, Akman HO, Quinzii CM, Zhang G. Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma. Nature Communications. 2021 Sep 1;12(1):5203.
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Ježek J, Cooper KF, Strich R. Reactive oxygen species and mitochondrial dynamics: the yin and yang of mitochondrial dysfunction and cancer progression. Antioxidants. 2018 Jan 16;7(1):13.
Zhao Y, Ye X, Xiong Z, Ihsan A, Ares I, Martínez M, Lopez-Torres B, Martínez-Larrañaga MR, Anadón A, Wang X, Martínez MA. Cancer metabolism: the role of ROS in DNA damage and induction of apoptosis in cancer cells. Metabolites. 2023 Jun 27;13(7):796.
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Sun Y, Shao C, Duan H, Wang Z, Xu S, Wang C, Xiu J, Liu J, Wang X, Yao X, Gao Y. Dynamic Evolution of the Tumor Immune Microenvironment in Malignant Tumors and Emerging Therapeutic Paradigms. MedComm. 2025 Dec;6(12):e70496.
Liang Y, Liu J, Feng Z. The regulation of cellular metabolism by tumor suppressor p53. Cell & bioscience. 2013 Feb 6;3(1):9.
Eriksson M, Ambroise G, Ouchida AT, Lima Queiroz A, Smith D, Gimenez-Cassina A, Iwanicki MP, Muller PA, Norberg E, Vakifahmetoglu-Norberg H. Effect of mutant p53 proteins on glycolysis and mitochondrial metabolism. Molecular and cellular biology. 2017 Dec 1;37(24):e00328-17.
Beyoğlu D, Idle JR. Metabolic rewiring and the characterization of oncometabolites. Cancers. 2021 Jun 10;13(12):2900.
Cai M, Zhao J, Ding Q, Wei J. Oncometabolite 2-hydroxyglutarate regulates anti-tumor immunity. Heliyon. 2024 Jan 30;10(2).
Beyoğlu D, Idle JR. Metabolic rewiring and the characterization of oncometabolites. Cancers. 2021 Jun 10;13(12):2900.
Baryła M, Semeniuk-Wojtaś A, Róg L, Kraj L, Małyszko M, Stec R. Oncometabolites—a link between cancer cells and tumor microenvironment. Biology. 2022 Feb 9;11(2):270.
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Mar 2, 2026
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How to Cite
Ubhenin, A. E., Idris, R. I., Adamude, F. A., & Ochalefu, D. O. (2026). Elucidating the Nexus of Mitochondrial Dysfunction and Oncometabolite Accumulation in Tumorigenesis. Nigerian Medical Journal, 67(2), 1295. https://doi.org/10.71480/nmj.v67i2.1295
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