Mitochondrial DNA Alterations in HPV-Related Cancers: Emerging Insights and Future Directions

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Abstract

Human papillomavirus (HPV) infection is a leading cause of cervical cancer and a significant contributor to anogenital and oropharyngeal malignancies worldwide. While the oncogenic functions of HPV oncoproteins E6 and E7 in disrupting nuclear tumor suppressor pathways are well established, their influence on mitochondrial biology has only recently emerged as a critical facet of HPV-driven carcinogenesis. This review synthesizes current evidence on the qualitative and quantitative alterations of mitochondrial DNA (mtDNA) and their functional consequences in HPV-associated cancers. We discuss how E6 and E7 modulate mitochondrial dynamics, bioenergetics, and redox balance, contributing to metabolic reprogramming, resistance to apoptosis, and adaptation to tumor microenvironmental stress. We also examine the clinical significance of mtDNA mutations, deletions, and copy number variations as potential biomarkers for diagnosis, prognosis, and therapy response. Advances in multi-omics approaches, high-throughput sequencing, and patient-derived organoid models have accelerated the exploration of mitochondria as therapeutic targets. Integrating mitochondrial profiling into HPV-related cancer research holds promise for identifying novel metabolic vulnerabilities and guiding the development of mitochondria-directed treatment strategies.

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  1. This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/17109184.

    Write a short summary of the research's main findings and how this work has moved the field forward.

    This preprint reviews evidence onon mitochondrial DNA (mtDNA) alterations in HPV-associated cancers, and specifically on copy number alterations, point mutations, and deletions. The alterations are explained relative to oxidative stress, apoptosis avoidance, and metabolic reprogramming, and are suggested to involve mitochondrial dysfunction in a supporting function in HPV-driven oncogenesis alongside viral oncogenes E6/E7.   The study contributes to the literature by putting mtDNA on a potential foundation for biomarkers and targets for therapy in HPV-related cancers.

    Major issues

    All of these findings are correlative and cannot clearly establish the causal participation of mtDNA compared to a side effect in HPV oncogenesis.

    Sparse explanation for why mtDNA changes are different between HPV-positive and HPV-negative cancers, that would resolve if such observations are virus-specific.

    While biomarkers for mtDNA are proposed, the preprint omits clearly presenting the practicability, technique-related problems, and verification required for use in the bedside

    Minor issues

    The paper is written more descriptively; a more formalized or critical reviews format (tables, figures, effect size) would make it more distinct.

    Competing interests

    The author declares that they have no competing interests.