Highlight
– Mitochondrial function in peripheral blood mononuclear cells (PBMCs) is significantly altered in Long COVID patients compared to controls.
– Long COVID is characterized by increased baseline and ATP-induced oxygen consumption but decreased responsiveness to oligomycin, suggesting aberrant ATP synthase activity.
– There are measurable correlations between mitochondrial dysfunction and clinical features, including autonomic health, quality of life, and duration since SARS-CoV-2 infection.
– Sex-specific differences in mitochondrial bioenergetics have been observed, indicating potential biological variability in the syndrome’s mitochondrial pathology.
Study Background and Disease Burden
The Long COVID syndrome presents a major ongoing healthcare challenge worldwide, with an estimated 10-20% of individuals infected by SARS-CoV-2 experiencing persistent symptoms exceeding one year after acute infection. Common debilitating symptoms include profound fatigue, exercise intolerance, and exertional hyperlactataemia, reminiscent of a systemic bioenergetic disturbance. Despite its high prevalence, the underlying pathophysiology of Long COVID remains incompletely understood. Emerging evidence suggests mitochondrial dysfunction as a plausible biological mechanism driving the clinical phenotype. Given mitochondria’s critical role in cellular energy metabolism, investigating their functional status in Long COVID could provide vital insights into disease mechanisms and therapeutic targets.
Study Design
In this prospective, case-controlled, observational study, 27 individuals with an established diagnosis of Long COVID were recruited from a single tertiary referral clinic, alongside 16 age-matched healthy controls aged 25-65 years. The inclusion criteria required confirmed prior SARS-CoV-2 infection with persistent symptoms consistent with Long COVID syndrome. Peripheral blood mononuclear cells (PBMCs) were isolated from participants’ blood samples and subjected to bioenergetic profiling using Seahorse extracellular flux analysis. This approach measured mitochondrial oxygen consumption rates (OCR) at baseline and in response to ATP induction and oligomycin inhibition, capturing aspects of mitochondrial respiratory capacity and ATP synthase activity. Clinical data including autonomic function, quality of life indices, and time elapsed since initial infection were collected and correlated with mitochondrial parameters. The study’s design enabled an integrated evaluation of cellular bioenergetic alterations and their relation to patient-reported clinical outcomes.
Key Findings
Long COVID cases exhibited a paradoxical mitochondrial profile characterized by increased baseline oxygen consumption rates as well as heightened ATP-induced OCR compared with controls, suggesting elevated mitochondrial respiratory activity. However, a significant attenuation in the tetramethylrhodamine methyl ester (TMRM) fluorescence response to oligomycin—a potent ATP synthase inhibitor—was observed, signifying an unusual adjustment in mitochondrial membrane potential regulation. These findings imply an altered ATP synthase function where the enzyme not only synthesizes ATP but also hydrolyzes it, possibly operating in both forward and reverse directions. This atypical activity may contribute to mitochondrial membrane potential maintenance rather than exclusive ATP production, revealing a distinctive bioenergetic phenotype in Long COVID.
Crucially, these mitochondrial functional metrics correlated with patient clinical profiles. Reduced mitochondrial efficiency aligned with poorer autonomic health and lower quality of life scores, while longer duration from the index infection corresponded with partial normalization of mitochondrial parameters, suggesting a dynamic disease trajectory. Additionally, sex-specific differences emerged, indicating biological variability that may influence mitochondrial response and symptomatology in Long COVID patients.
Expert Commentary
This study significantly advances understanding of Long COVID by providing direct evidence of mitochondrial dysregulation at the cellular level, implicating ATP synthase dysfunction as a central pathological mechanism. The notion that ATP synthase may perform dual roles in energy synthesis and hydrolysis introduces novel perspectives on mitochondrial bioenergetics in chronic post-viral illness. While Seahorse flux analyses in PBMCs offer a feasible surrogate for systemic mitochondrial function assessment, further investigation in tissue-specific contexts is warranted.
Limitations include the relatively small sample size and single-center recruitment, which may limit generalizability. Longitudinal studies will be essential to establish causality and temporal mitochondrial changes over disease progression. The observed sex differences underscore the need for personalized approaches in managing Long COVID. Integrating mechanistic insights with clinical phenotypes enhances the potential for identifying biomarkers and therapeutic targets tailored to mitochondrial restoration.
Conclusion
The study by Macnaughtan et al. provides compelling evidence that mitochondrial function, specifically ATP synthase activity, is impaired in Long COVID patients and correlates with clinical manifestations such as autonomic dysfunction and quality of life impairment. This bioenergetic dysfunction may underlie key symptoms like fatigue and exercise intolerance. The findings open avenues for mitochondrial-targeted therapies and highlight the importance of further validating these observations in larger, multi-center cohorts with longitudinal follow-up. Understanding mitochondrial contributions to Long COVID pathophysiology is paramount for developing effective interventions to alleviate this global health burden.
References
Macnaughtan J, Chau KY, Brennan E, Toffoli M, Spinazzola A, Hillman T, Heightman M, Schapira AHV. Mitochondrial function is impaired in long COVID patients. Ann Med. 2025 Dec;57(1):2528167. doi: 10.1080/07853890.2025.2528167. Epub 2025 Aug 12. PMID: 40792393; PMCID: PMC12344680.
