Mitochondrial Genetics and Cancer Metabolism

Mitochondria are central hubs of cellular bioenergetics, biosynthesis and signalling, governed by dual genetic control from both nuclear DNA and mitochondrial DNA (mtDNA). In cancer, mutations in mtDNA and in nuclear-encoded mitochondrial genes can reprogramme energy metabolism, shifting the balance between oxidative phosphorylation and glycolysis to meet the demands of rapid proliferation. Altered respiratory function often leads to increased production of reactive oxygen species (ROS), which in turn can drive genomic instability, influence hypoxia-responsive pathways and shape the tumour microenvironment. Metabolic heterogeneity among cancer types reflects differences in mitochondrial proteome composition, substrate utilisation and adaptive signalling through energy sensors such as AMP-activated protein kinase (AMPK). Together, genetic lesions and dynamic metabolic remodelling underpin novel vulnerabilities that are now being explored for selective therapeutic intervention, with the goal of disrupting tumour-specific mitochondrial functions while sparing normal tissues.

Research from Nature Portfolio

Recent mitochondrial phenotyping across multiple murine tumour models has revealed that intrinsic expression and function of oxidative phosphorylation complexes are consistently lower in cancers than in matched normal tissues or highly oxidative organs. Despite overall suppression of OXPHOS, cancer types display marked heterogeneity in mitochondrial proteome composition and substrate-specific flux, pointing towards the feasibility of targeting discrete mitochondrial proteins or pathways unique to particular cancers. In another study of thyroid tumours characterised by near-homozygous genomes, functional impairment of respiratory complex I was shown to elevate superoxide generation and reduce glycolytic activity, while sustaining cell survival through alternative anaplerotic routes such as reductive carboxylation. These findings illuminate a direct link between mitochondrial dysfunction, ROS-induced chromosomal instability and metabolic reprogramming in cancer.

Mitochondrial Genetics and Cancer Metabolism publication trend

The graph below shows the total number of articles in mitochondrial genetics and cancer metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Mitochondrial DNA (mtDNA): The small circular genome within mitochondria encoding key subunits of the oxidative phosphorylation machinery.

Oxidative phosphorylation (OXPHOS): The process by which electrons from metabolic substrates drive ATP synthesis via the mitochondrial respiratory chain.

Respiratory Complex I: The first enzyme of the mitochondrial electron transport chain that oxidises NADH and contributes to the proton gradient.

Reactive oxygen species (ROS): Highly reactive molecules derived from oxygen that can damage biomolecules and modulate signalling pathways.

Warburg effect: The tendency of cancer cells to favour aerobic glycolysis over oxidative phosphorylation for energy production.

Heteroplasmy: The coexistence of more than one type of mtDNA sequence within a cell or tissue.

References

1. Pan-tissue mitochondrial phenotyping reveals lower OXPHOS expression and function across cancer types. Scientific Reports (2023).
2. Mitochondrial metabolism and energy sensing in tumor progression. Biochimica et Biophysica Acta (BBA) - Bioenergetics (2017).
3. Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma. eLife (2019).
4. Metabolic reprogramming related to whole-chromosome instability in models for Hürthle cell carcinoma. Scientific Reports (2020).
5. Respiratory Complex I dysfunction in cancer: from a maze of cellular adaptive responses to potential therapeutic strategies. The FEBS Journal (2021).