Circulating Cell-Free Mitochondrial DNA in Long COVID
1 Matits et al. 2026 — Circulating cf-mtDNA, Cognition, and Inflammation in Long COVID
Full Citation:: Matits L, et al.; EPILOC Phase 2 Study Group. Circulating mitochondrial and cellular damage markers in long COVID: Links to cognitive function, psychological distress, and inflammation. Molecular Psychiatry. 2026. Online ahead of print. DOI:: 10.1038/s41380-026-03471-0 PMID:: 41654652 Published:: February 7, 2026 (online ahead of print) Study Design:: Nested case-control study within the EPILOC (Epidemiology of Long COVID) population-based cohort, Baden-Württemberg, Germany Sample Size:: n=228 (PASC/Long COVID n=128; recovered controls n=100) Key Findings::
- Long COVID (PASC) patients had lower relative circulating cell-free mitochondrial DNA (ccf-mtDNA) than recovered controls
- After full covariate adjustment: F(1,192)=2.92; p=0.089; partial η²=0.01 (borderline non-significant)
- Excluding high-CRP participants (>10 mg/L): F(1,181)=4.36; p=0.038; partial η²=0.02 (just significant; very small effect)
- General cognition correlated positively with ccf-mtDNA (less ccf-mtDNA associated with worse cognition)
- CRP correlated negatively with ccf-mtDNA (higher inflammation associated with less ccf-mtDNA)
- Total cell-free DNA was not elevated — the reduction is mitochondria-specific
- 25% of PASC patients showed low-grade inflammation (elevated CRP)Conclusion:: Reduced ccf-mtDNA in Long COVID may reflect impaired mitophagy (altered mitochondrial quality control) rather than reduced cellular damage, potentially causing intracellular accumulation of damaged mitochondria and chronic energy deficits. Physical deconditioning is an alternative explanation, as ccf-mtDNA rises physiologically with exercise. Relevance to ME/CFS:: This finding is directly relevant to the ME/CFS vs Long COVID comparison. In contrast, Tsilioni et al.~(Tsilioni, Natelson, and Theoharides 2022) (2022) found exosome-associated mtDNA elevated in ME/CFS serum after exercise challenge (not at rest). This directional difference — reduced free cf-mtDNA in Long COVID at rest vs elevated exosome-associated mtDNA in ME/CFS post-exercise — is intriguing but not established as a distinguishing biomarker: measurements use different compartments, different timing, and no direct head-to-head comparison exists. Limitations:: Very small effect sizes; marginal statistical significance; heterogeneous PASC definition; physical activity confound not fully excluded; multiple comparisons without p-value correction; only second study of cf-mtDNA in PASC. Certainty Assessment::
- *Quality:* Medium-High (population-based cohort, n=228, high-impact peer-reviewed journal)
- *Effect size:* Very small (partial η²=0.01--0.02)
- *Replication:* Not replicated; only second PASC study (prior: Szögi 2024, n=5)
- *Conflicts of interest:* None declared
- *Certainty:* 0.35 (for distinguishing Long COVID from ME/CFS claim); 0.50 (for reduced ccf-mtDNA observation in PASC)2 Szögi et al. 2025 — Novel Mitochondrial Dysfunction Biomarkers in Long COVID
Full Citation:: Szögi T, Borsos BN, Masic D, et al. Novel biomarkers of mitochondrial dysfunction in Long COVID patients. GeroScience. 2025;47(2):2245–2261. DOI:: 10.1007/s11357-024-01398-4 PMID:: 39495479 Published:: Epub November 2024; published April 2025 Study Design:: Small comparative study using transmission electron microscopy and biomarker analysis Sample Size:: n=10 (5 Long COVID patients, 5 controls with secondary ciliary dyskinesia) Key Findings::
- Reduced circulating cell-free mitochondrial DNA (ccf-mtDNA) in Long COVID patients — first study to report this finding in PASC
- Mitochondrial ultrastructural abnormalities: significant swelling, disrupted cristae, irregular morphology
- Elevated superoxide dismutase 1 (SOD1) and autophagy-related 4B cysteine peptidase (ATG4B)
- Five mitochondrial genes analyzed: MTATP6, MTCYTB, MTND1, MTND4, MTND5Conclusion:: Mitochondrial structural and functional abnormalities persist in Long COVID, with ccf-mtDNA serving as a candidate biomarker. Elevated ATG4B may indicate autophagy dysregulation. Relevance:: First study to demonstrate reduced ccf-mtDNA in PASC; replicated directionally by Matits et al.~(Matits, others, and EPILOC Phase 2 Study Group 2026) in a much larger cohort. Provides ultrastructural evidence supporting mitochondrial pathology in Long COVID. Limitations:: Extremely small sample (n=5 per group); controls have secondary ciliary dyskinesia (atypical comparison group); tissue biopsy rather than blood sample; highly selected patient population for olfactory symptoms. Certainty Assessment::
- *Quality:* Low (n=5, highly selected sample, atypical control group)
- *Replication:* Directionally replicated in larger cohort (Matits 2026)