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. 2024 Apr 18.
doi: 10.1007/s11764-024-01590-7. Online ahead of print.

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

Amy M Berkman  1 , Chelsea G Goodenough  2 , Paul Durakiewicz  2 , Carrie R Howell  3 , Zhaoming Wang  2   4 , John Easton  4 , Heather L Mulder  4 , Gregory T Armstrong  2 , Melissa M Hudson  1   2 , Mondira Kundu  5 , Kirsten K Ness  6
Affiliations

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

Amy M Berkman et al. J Cancer Surviv. .

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.

Keywords: Biomarkers; Cardiac dysfunction; Childhood cancer survivors; Mitochondrial DNA copy number.

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