Circulating Mitochondrial DNA Is Associated With High Levels of Fatigue in Two Independent Sarcoidosis Cohorts.

BACKGROUND: Patients with sarcoidosis who develop severe clinical phenotypes of pulmonary fibrosis or multiorgan disease experience debilitating symptoms, with fatigue being a common chief complaint. Studies that have investigated this patient-related outcome measure (PROM) have used the Fatigue Assessment Scale (FAS), a self-reported questionnaire that reflects mental and physical domains. Despite extensive work, its cause is unknown and treatment options remain limited. Previously, we showed that the plasma of patients with sarcoidosis 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 that connects sarcoidosis-induced fatigue and mtDNA-mediated TLR9 activation? STUDY DESIGN AND METHODS: Using a local cohort of patients at Yale (discovery cohort) and the National Institutes of Health-sponsored Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis study (validation cohort), we scored the FAS and quantified in the plasma, mtDNA concentrations, TLR9 activation, and cytokine levels. RESULTS: Although FAS scores were independent of corticosteroid use and Scadding stage, we observed a robust association between FAS scores, which included mental and physical domains, and multiorgan 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. Last, 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. Mechanistic work that investigates 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.

α1 Adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is increasingly associated with nerve-driven processes and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here, we report that noradrenaline (NA) derived from the lung's adrenergic nerve supply drives α-smooth muscle actin (αSMA)-expressing fibroblast accumulation via mechanisms involving α1 adrenoreceptors and mtDNA. Using the bleomycin model, we compared ablation of the lung's adrenergic nerve supply with surgical adrenal resection and found that NA derived from local but not adrenal sources contributes to experimentally induced lung fibrosis and the emergence of an αSMA+ve fibroblast population expressing adrenoreceptor α-1D (ADRA1D). Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed these changes and suppressed extracellular mtDNA accumulation. Cultured normal human lung fibroblasts displayed α1 adrenoreceptors and in response to costimulation with TGFß1 and NA adopted ACTA2 expression and extracellular mtDNA release. These findings were opposed by terazosin. Evaluation of a previously studied IPF cohort revealed that patients prescribed α1 adrenoreceptor antagonists for nonpulmonary indications demonstrated improved survival and reduced concentrations of plasma mtDNA. Our observations link nerve-derived NA, α1 adrenoreceptors, extracellular mtDNA, and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuroinnate connection may yield new avenues for investigation in the clinical and basic science realms.

Mitochondrial DNA Sensing Pathogen Recognition Receptors in Systemic Sclerosis Associated Interstitial Lung Disease: A Review.

Purpose of the review: Systemic sclerosis (SSc) is a condition of dermal and visceral scar formation characterized by immune dysregulation and inflammatory fibrosis. Approximately 90% of SSc patients develop interstitial lung disease (ILD), and it is the leading cause of morbidity and mortality. Further understanding of immune-mediated fibroproliferative mechanisms has the potential to catalyze novel treatment approaches in this difficult to treat disease. Recent findings: Recent advances have demonstrated the critical role of aberrant innate immune activation mediated by mitochondrial DNA (mtDNA) through interactions with toll-like receptor 9 (TLR9) and cytosolic cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS). Summary: In this review, we will discuss how the nature of the mtDNA, whether oxidized or mutated, and its mechanism of release, either intracellularly or extracellularly, can amplify fibrogenesis by activating TLR9 and cGAS, and the novel insights gained by interrogating these signaling pathways. Because the scope of this review is intended to generate hypotheses for future research, we conclude our discussion with several important unanswered questions.

Relationship between sleep disturbances, lipid profile and insulin sensitivity in type 1 diabetic patients: a cross-sectional study

ABSTRACT Objective The consequences of sleep deprivation in type 1 diabetes (T1D) patients are poorly understood. Our aim was to determine how sleep disorders influence lipid profile and insulin sensitivity in T1D patients. Materials and methods This was a cross-sectional study at a public university hospital. Demographic information and medical histories were obtained during regular scheduled visit of T1D patients to the outpatient clinic. Insulin sensitivity was obtained using the estimated glucose disposal rate (eGDR) formula. Sleep quality was assessed using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Berlin Questionnaire. Results The adult participants (n = 66, 62% women) had a median age of 28.0 years (interquartile range 21.8-33.0). Six patients (9%) had metabolic syndrome according to the International Diabetes Federation criteria. Thirty patients (46%) were considered poor sleepers according to the Pittsburgh Sleep Quality Index. The LDL-c and total cholesterol levels of poor sleepers were higher than those of good sleepers (103 v. 81; p = 0.003 and 178.0 v. 159.5 mg/dL; p = 0.009, respectively). Three patients (4%) were at high risk of obstructive sleep apnea syndrome (OSAS) according to the Berlin Questionnaire. The eGDR was lower in the group of patients with high probability of having OSAS (6.0 v. 9.1 mg.kg-1.min-1;p = .03). Conclusions Poor subjective quality of sleep and higher risk of OSAS were correlated with a worsened lipid profile and decreased insulin sensitivity, respectively. Therefore, T1D patients with sleep disturbances might have an increased cardiovascular risk in the future.

Relationship between sleep disturbances, lipid profile and insulin sensitivity in type 1 diabetic patients: a cross-sectional study.

Objective The consequences of sleep deprivation in type 1 diabetes (T1D) patients are poorly understood. Our aim was to determine how sleep disorders influence lipid profile and insulin sensitivity in T1D patients. Materials and methods This was a cross-sectional study at a public university hospital. Demographic information and medical histories were obtained during regular scheduled visit of T1D patients to the outpatient clinic. Insulin sensitivity was obtained using the estimated glucose disposal rate (eGDR) formula. Sleep quality was assessed using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Berlin Questionnaire. Results The adult participants (n = 66, 62% women) had a median age of 28.0 years (interquartile range 21.8-33.0). Six patients (9%) had metabolic syndrome according to the International Diabetes Federation criteria. Thirty patients (46%) were considered poor sleepers according to the Pittsburgh Sleep Quality Index. The LDL-c and total cholesterol levels of poor sleepers were higher than those of good sleepers (103 v. 81; p = 0.003 and 178.0 v. 159.5 mg/dL; p = 0.009, respectively). Three patients (4%) were at high risk of obstructive sleep apnea syndrome (OSAS) according to the Berlin Questionnaire. The eGDR was lower in the group of patients with high probability of having OSAS (6.0 v. 9.1 mg.kg-1.min-1;p = .03). Conclusions Poor subjective quality of sleep and higher risk of OSAS were correlated with a worsened lipid profile and decreased insulin sensitivity, respectively. Therefore, T1D patients with sleep disturbances might have an increased cardiovascular risk in the future.