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Associations between mitochondrial copy number, exercise capacity, physiologic cost of walking, and cardiac strain in young adult survivors of childhood cancer

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Abstract

Purpose

Childhood cancer survivors are at risk for cardiac dysfunction and impaired physical performance, though underlying cellular mechanisms are not well studied. In this cross-sectional study, we examined the association between peripheral blood mitochondrial DNA copy number (mtDNA-CN, a proxy for mitochondrial function) and markers of performance impairment and cardiac dysfunction.

Methods

Whole-genome sequencing, validated by quantitative polymerase chain reaction, was used to estimate mtDNA-CN in 1720 adult survivors of childhood cancer (48.5% female; mean age = 30.7 years, standard deviation (SD) = 9.0). Multivariable logistic regression was performed to evaluate the associations between mtDNA-CN and exercise intolerance, walking inefficiency, and abnormal global longitudinal strain (GLS), adjusting for treatment exposures, age, sex, and race and ethnicity.

Results

The prevalence of exercise intolerance, walking inefficiency, and abnormal GLS among survivors was 25.7%, 10.7%, and 31.7%, respectively. Each SD increase of mtDNA-CN was associated with decreased odds of abnormal GLS (adjusted odds ratio (OR) = 0.88, p = 0.04) but was not associated with exercise intolerance (OR = 1.02, p = 0.76) or walking inefficiency (OR = 1.06, p = 0.46). Alkylating agent exposure was associated with increased odds of exercise intolerance (OR = 2.25, p < 0.0001), walking inefficiency (OR = 2.37, p < 0.0001), and abnormal GLS (OR = 1.78, p = 0.0002).

Conclusions

Increased mtDNA-CN is associated with decreased odds of abnormal cardiac function in childhood cancer survivors.

Implications for Cancer Survivors

These findings demonstrate a potential role for mtDNA-CN as a biomarker of early cardiac dysfunction in this population.

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Data availability

The data that support the findings of this study are opening available at https://www.stjude.cloud/research-domains/cancer-survivorship. Data specific for this paper will be uploaded to https://zenodo.org concomitant with publication of the manuscript.

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Acknowledgements

The authors would like to thank Tracie Gatewood for formatting assistance and manuscript preparation.

Funding

This work was supported by grants provided by the National Cancer Institute (CA195547, MMH and KKN; CA174851 KKN), the Cancer Center Support Grant (CA21765, CRR), and the American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Amy M. Berkman & Melissa M. Hudson

  2. Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS-735, Memphis, TN, 38105, USA

    Chelsea G. Goodenough, Paul Durakiewicz, Zhaoming Wang, Gregory T. Armstrong, Melissa M. Hudson & Kirsten K. Ness

  3. Division of Preventive Medicine, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Carrie R. Howell

  4. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Zhaoming Wang, John Easton & Heather L. Mulder

  5. Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Mondira Kundu

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  1. Amy M. Berkman
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Contributions

AB: writing—original draft; CG: data curation, formal analysis; PD; writing—original draft; CH: writing—review and editing; ZW: conceptualization, writing—review and editing; JE: data curation; HM: data curation; GA: supervision; MH: funding, writing—review and editing, supervision; MK: conceptualization, writing—review and editing; KN: conceptualization, data curation, funding, formal analysis, writing—original draft.

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Correspondence to Kirsten K. Ness.

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Berkman, A.M., Goodenough, C.G., Durakiewicz, P. et al. Associations between mitochondrial copy number, exercise capacity, physiologic cost of walking, and cardiac strain in young adult survivors of childhood cancer. J Cancer Surviv (2024). https://doi.org/10.1007/s11764-024-01590-7

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