Phase-dependent dynamics of circulating cell-free mitochondrial DNA reflect distinct immunometabolic states.

Authors

Karen Alessandra Rodrigues, Emilly Henrique Dos Santos, Gabriel Acca Barreira, Mariana Okay Saippa, Maria Carolina Pires Cruz, Kelly Aparecida Kanunfre, Thelma Suely Okay

Published in

Revista do Instituto de Medicina Tropical de Sao Paulo. Volume 68. Pages e48. Epub Jul 24, 2026.

Abstract

Circulating cell-free mitochondrial DNA (ccf-mtDNA) has emerged as a potential biomarker of tissue injury and systemic inflammation, acting as a mitochondrial damage-associated molecular pattern (DAMP) capable of activating innate immune pathways. However, most studies have focused on acute inflammatory conditions, and the behavior of ccf-mtDNA across distinct immunological and metabolic disease states remains poorly characterized, particularly in pediatric populations. This study investigated whether circulating ccf-mtDNA levels vary according to the clinical and immunometabolic context rather than simply reflecting the presence of inflammation. Serum ccf-mtDNA copy number was quantified by quantitative polymerase chain reaction (qPCR) targeting the mitochondrial ND2 gene in 181 clinical samples obtained from five groups: adults with chronic-active and/or treatment-refractory pulmonary tuberculosis (n = 47); asymptomatic children with latent tuberculosis infection confirmed by interferon-gamma release assay (IGRA) without clinical, radiological or microbiological evidence of active disease (n = 11); children with severe chronic underlying diseases in clinically stable condition (n = 41); children undergoing cardiac surgery with cardiopulmonary bypass (CPB), with perioperative serial sampling (n = 52); and healthy young adult blood donors as controls (n = 30). Non-parametric statistical tests were applied due to non normal data distribution. Median ccf-mtDNA levels in controls were 649.3 copies/μL. Adults with chronic-active pulmonary and/or treatment-refractory tuberculosis and children undergoing cardiac surgery with CPB did not exhibit significantly elevated ccf-mtDNA levels compared with controls. In contrast, significantly higher levels were observed in IGRA-positive children with latent tuberculosis infection (median: 1,648.5 copies/μL; p = 0.0004) and in children with severe chronic underlying diseases despite the absence of overt infection or inflammation (median: 2,663.9 copies/μL; p = 0.0001). These findings suggest that circulating ccf-mtDNA does not behave as a simple linear marker of inflammatory intensity. Instead, its levels appear to reflect the interaction between mitochondrial injury, immune activation, metabolic competence, and clearance mechanisms. We propose a phase-dependent model in which mitochondrial DAMP signaling is amplified during sustained but metabolically competent immune engagement, and is attenuated during advanced immunometabolic exhaustion. These findings suggest that ccf-mtDNA levels are shaped by the host's underlying immunometabolic context, rather than simply mirroring the intensity of systemic inflammation.

PMID:
42525119
Bibliographic data and abstract were imported from PubMed on 29 Jul 2026.

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