Mitochondrial function is impaired in long COVID patients, 2025, Macnaughtan, Heightman+

[SNT Gatchaman]

Mitochondrial function is impaired in long COVID patients

Spoiler: Authors

Jane Macnaughtan; Kai-Yin Chau; Ewen Brennan; Marco Toffoli; Antonella Spinazzola; Toby Hillman; Melissa Heightman; Anthony Henry Vernon Schapira

BACKGROUND
The Long COVID syndrome is a major global health problem, affecting approximately 10–20% of individuals infected with SARS-CoV-2 virus with many remaining symptomatic beyond one year. Fatigue, reduced exercise tolerance and hyperlactataemia on minimal exertion have led to the suggestion of a bioenergetic defect. We hypothesised that mitochondrial dysfunction is a pathological feature in Long COVID cases and would correlate with clinical outcome.

METHODS
This prospective, case-controlled, observational study recruited 27 participants with an established diagnosis of Long COVID syndrome from a single tertiary clinic together with 16 age-matched controls aged 25–65 years. Seahorse-based mitochondrial flux analysis and bioenergetics profile of isolated peripheral blood mononuclear cells (PBMCs) was performed and correlated with clinical phenotype.

FINDINGS
Long COVID cases had an increased baseline and ATP-induced oxygen consumption rate with a significant attenuation in tetramethylrhodamine methyl ester perchlorate fluorescence response to oligomycin. Correlations were observed between mitochondrial function and autonomic health, quality of life and time from index infection. Sex-specific differences were also observed.

INTERPRETATION
PBMCs from Long COVID subjects exhibit an exceptional and distinctive change in ATP synthase, as it contributes to the mitochondrial membrane potential rather than using it exclusively to generate ATP. The findings suggest that the enzyme runs both forward and reverse reactions, synthesising and hydrolysing ATP. The correlation of mitochondrial function with clinical phenotype in Long COVID may indicate a causal relationship and warrants further validation in larger scale studies.

Web | PDF | Annals of Medicine | Open Access

 

[wigglethemouse]

In the discussion they have a section titled "PBMC complex V activity is aberrant in long COVID". This paper might be relevant to your work @DMissa

 

[DMissa]

In the discussion they have a section titled "PBMC complex V activity is aberrant in long COVID". This paper might be relevant to your work @DMissa

Sadly I don't know what can really be drawn from the study in terms of mitochondrial function differences

There's no mention of PEM, and they're reporting negative proton leak values which means they have larger OCR values at the end of the assay than post-oligomycin, which doesn't really make biological sense. This does happen in seahorse but in my view those observations should be excluded from interpretation as artefacts. There's also the common combination of rotenone and antimycin A which means that pulling out the individual targets of those drugs (such as the contribution of complex 1 to OCR) is impossible. They've stained with TMRM but not with a total membrane dye to normalise back to, so the membrane potential results cannot be disentangled from potential differences in membrane content (CS and TOM20 are proxies which do not directly address membrane volume and I can't tell whether those were normalised against). If there is a mitochondrial issue as hypothesised, particularly in biogenesis, any potentially assumed balance here could easily be broken.

The main differences are elevated basal respiration and post-oligomycin respiration (ATP synthesis-attributable oxygen consumption) which to me suggests different proportions of immune cell populations with different generalised levels of respiration (which we know very well that they have). I don't see anything about quantifying this in the paper so I think the safe conclusion is that it is likely that there are shifts in proportions of different cells in the PBMCs of the sampled individuals, which may be explicable by many factors.

 

[SNT Gatchaman]

From limitations —

Our study was designed as a pilot study and as such, has a number of limitations. Sample size was relatively small and whilst the groups were matched for age, there were differences between the groups with regards to BMI, ethnicity and male to female ratio with the potential to introduce confounding factors.

The study also did not further characterise the individual monocyte and lymphocyte subsets of the PBMC population and would be an important focus of future studies.