Prokaryotic organelle mitochondria drive tumorigenesis - “the original sin”

Sep 22, 2026

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Mitochondria retain bacterial traits from their endosymbiotic origin, and cancer-cell alterations can mirror prokaryotic-like characteristics. A central example is the Warburg effect, where tumors rely on aerobic glycolysis rather than oxidative phosphorylation, alongside disruptions such as an uncoupled electron transport chain and a truncated TCA cycle. TCA intermediates can regulate genes for differentiation, apoptosis, and tumor suppression, while supporting glycolysis, angiogenesis, and resistance to death.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Endosymbiotic origin of mitochondria

Cancer as a metabolic disorder

Warburg effect and mitochondrial dysfunction

TYPE Review PUBLISHED 02 January 2026 DOI 10.3389/fonc.2025.1632702 OPEN ACCESS EDITED BY Nadia Judith Jacobo-Herrera, National Institute of Medical Sciences and Nutrition Salvador Zubira´n, Mexico REVIEWED BY Davide Gnocchi, Saint Camillus International University of Health and Medical Sciences, Italy Marvin Edeas, INSERM U1016 Institut Cochin, France *CORRESPONDENCE Fangyan Wang [fangyan_wang@wmu.edu.cn](fangyan_wang@wmu.edu.cn)[ ](fangyan_wang@wmu.edu.cn)Xiangyang Xue [wzxxy001@163.com](wzxxy001@163.com) RECEIVED 21 May 2025 REVISED 07 November 2025 ACCEPTED 26 November 2025 PUBLISHED 02 January 2026 CITATION Wang C, Luo M, Zhou J, Zhang Q, Ji X, He J, Wang L, Huang Y, Xue X and Wang F (2026) Prokaryotic organelle mitochondria drive tumorigenesis: “the original sin”. Front. Oncol. 15:1632702 . doi: 10.3389/fonc.2025.1632702 COPYRIGHT © 2026 Wang, Luo, Zhou, Zhang, Ji, He, Wang, Huang, Xue and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Prokaryotic organelle mitochondria drive tumorigenesis: “the original sin” Chaoyi Wang 1, Ming Luo 1, Jinhui Zhou 1, Qihao Zhang 1, Xiawei Ji 1, Jiayao He 1, Lingfei Wang 1, Yingpeng Huang 1, Xiangyang Xue 2,3* and Fangyan Wang 2,3* 1The Second Afﬁliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China, 2Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Afﬁliated Hospital, Wenzhou Medical University, Wenzhou, China, 3 Institute of Inhaled Diagnosis and Therapeutics for Interstitial Lung Disease, Institute of Microbiota and Host Inﬂammation-related Diseases, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China Mitochondria preserve bacterial traits because of their endosymbiotic origin, and their alterations in cancer cells reﬂect these prokaryotic-like traits. One such trait is the Warburg effect, wherein tumor cells rely primarily on aerobic glycolysis instead of oxidative phosphorylation. Cancer cells also exhibit metabolic abnormalities, such as an uncoupled electron transport chain and a truncated tricarboxylic acid (TCA) cycle, potentially generating additional energy. Intermediates from the disrupted TCA cycle can regulate key genes involved in cell differentiation, apoptosis, and tumor suppression while promoting aerobic glycolysis, angiogenesis, and resistance to cell death. Mitochondria-related gene mutations, particularly in D-loop and TCA-related enzymes, have been identiﬁed as key drivers of prokaryotic transformation in diverse cancers. Furthermore, the metabolic activity of cancer mitochondria results in the production of essential biosynthetic precursors for nucleotide synthesis and lipid synthesis, supporting tumor growth. Mitochondria also contribute to tumorigenesis by promoting inﬂammation and iron metabolism disorders. Mitochondrial dysfunctions have raised interest in the use of mitochondria-targeted anticancer strategies as possible cancer treatments, although their clinical application requires further investigation. KEYWORDS mitochondria, cancer, endosymbiosis theory, Warburg effect, TCA cycle 1 Introduction Cancer has caused more than ten million mortalities annually worldwide, making it the second leading cause of death. Chemotherapy and radiotherapy still destroy healthy cells, causing toxicity and leading to an immense economic burden on patients. Considering the unsatisfactory cancer survival rate, exploration of epigenetic changes and further investigations into the mechanisms of tumorigenesis ar

FAQs

What does the review state about mitochondria in cancer cells?

It explains that mitochondria preserve bacterial traits from their endosymbiotic origin and that cancer cells show mitochondrial alterations resembling prokaryotic-like features.

How does the Warburg effect relate to tumorigenesis in the review?

The review describes the Warburg effect as a key metabolic trait of tumors, where cells preferentially use aerobic glycolysis instead of oxidative phosphorylation.

Why are changes in the TCA cycle important according to the review?

Disrupted or truncated TCA cycle activity can generate intermediates that regulate genes involved in differentiation, apoptosis, and tumor suppression, while also promoting glycolysis, angiogenesis, and resistance to cell death.

Sep 22, 2026

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