Circulating Mitochondrial DNA is associated with High Levels of Fatigue in Two Independent Sarcoidosis Cohorts 2023 Fiorini et al

Background
Sarcoidosis patients who develop severe clinical phenotypes of pulmonary fibrosis or multi-organ disease experience debilitating symptoms, with fatigue being a common chief complaint. Studies investigating this patient-related outcome measure (PROM) have employed the Fatigue Assessment Scale (FAS), a self-reported questionnaire that reflects mental and physical domains. Despite extensive work, its etiology is unknown and treatment options remain limited. Previously, we showed that the plasma of sarcoidosis patients with extrapulmonary disease endorsing fatigue was enriched for mitochondrial DNA (mtDNA), a ligand for the innate immune receptor Toll-like Receptor 9 (TLR9). Through our cross-disciplinary platform, we investigated a relationship between sarcoidosis-induced fatigue and circulating mtDNA.

Research Question
Is there a psychobiologic mechanism connecting sarcoidosis-induced fatigue and mtDNA-mediated TLR9 activation?

Study Design and Methods
Using a local cohort of patients at Yale (discovery cohort) and the NIH-sponsored GRADS study (validation cohort), we scored the FAS and quantified in the plasma mtDNA concentrations, TLR9 activation, and cytokine levels.

Results
While FAS scores were independent of corticosteroid use and Scadding Stage, we observed a robust association between FAS scores, including mental and physical domains, and multi-organ sarcoidosis. Subsequently, we identified a significant correlation between plasma mtDNA concentrations and all domains of fatigue. Additionally, we found that TLR9 activation is associated with all aspects of the FAS and partially mediates this PROM through mtDNA. Lastly, we found that TLR9 associated soluble mediators in the plasma are independent of all facets of fatigue.

Interpretation
Through our cross-disciplinary translational platform, we identified a previously unrecognized psychobiologic connection between sarcoidosis-induced fatigue and circulating mtDNA concentrations potentially mediated by TLR9 activation. Mechanistic work investigating the contribution of mtDNA-mediated innate immune activation in this PROM, and clinical studies with prospective cohorts, has the potential to catalyze novel therapeutic strategies for this patient population and those with similar conditions.

Paywall, https://journal.chestnet.org/article/S0012-3692(23)05793-8/pdf

 

I don’t have the capacity to understand this study. From first glance I wonder is it saying that circulating mtDNA does cause fatigue? Or is it still too early to say that?

Also ‘psychobiologic’, does that have a variety of meanings, because I just looked it up and the definition was all about the mind relating to the brain. And BPS stuff. Seems a bit contradictory to the findings of this study.

Or is it just that fatigue is always considered/labelled as “psycho” why would that be? Because your mind gets worn out? Or is any subjective symptom a psycho thing?
Is that why pain and gut dysfunction and nausea are considered psychological by our Drs?
Is this why fatigue is considered evidence of mental illness by so many doctors?
Is being fatigued being considered a mental illness by doctors and researchers why doctors also might think ME is a mental illness, because we’re fatigued and that’s psycho?