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Abstract Mitokines (Humanin (HN), GDF15 and FGF21) are produced as a result of mitochondrial dysfunction and may have major roles in chronic inflammation, malnutrition and exercise capacity in people with COPD. Except for GDF15, studies on this subject are lacking. A total of 165 patients with stable COPD and 49 smokers without COPD were enrolled. We assessed their serum mitokine levels and clinical characteristics at baseline. We recorded moderate and severe exacerbation for the next 12 months. Baseline serum HN (p = 0.037) and GDF-15 (p = 0.013) levels were higher in the COPD group. High HN levels were independently associated with a high risk of exacerbation (HRE) (OR 2.798, 95% CI 1.266–6.187, p = 0.011), malnutrition (OR 6.645, 95% CI 1.859–23.749, p = 0.004), and 6MWD (OR 0.995, 95% CI 0.991–0.999, p = 0.008), and future moderate (HR 1.826, 95% CI 1.181–2.822, p = 0.007) and severe exacerbations (HR 3.445, 95% CI 1.357–8.740, p = 0.009). High GDF15 levels were associated with HRE (OR 3.028, 95% CI 1.134–8.083, p = 0.027), 6MWD (OR 0.995, 95% CI 0.990–0.999, p = 0.017) and predicted desaturation in 6MWT (OR 3.999, 95% CI 1.487–10.757, p = 0.006). High FGF21 levels were associated with HRE (OR 2.144, 95% CI 1.000–4.600, p = 0.05), and predicted future severe exacerbation (HR 4.217, 95% CI 1.459–12.193, p = 0.008). The mitokine levels were higher in patients with COPD than smokers without COPD, and were associated with important clinical outcomes such as exercise capacity and COPD exacerbation. Among the mitokines, HN showed the strongest association with COPD and may serve as a future risk biomarker in this disease. Trial registation NCT04449419.

BackgroundMOTS-c and Romo1 are mitochondrial peptides that are modulated by oxidative stress. No previous studies have explored circulating levels of MOTS-c in patients with chronic obstructive pulmonary disease (COPD).MethodsWe enrolled 142 patients with stable COPD and 47 smokers with normal lung function in an observational cross-sectional study. We assessed serum levels of both MOTS-c and Romo1 and associated these findings with clinical characteristics of COPD.ResultsCompared with smokers with normal lung function, patients with COPD had lower levels of MOTS-c (p = 0.02) and higher levels of Romo1 (p = 0.01). A multivariate logistic regression analysis revealed that above-median MOTS-c levels were positively associated with Romo1 levels (OR 1.075, 95% CI 1.005–1.150, p = 0.036), but no association was found with other COPD characteristics. Below-median levels of circulating MOTS-c were associated with oxygen desaturation (OR 3.25 95% CI 1.456–8.522, p = 0.005) and walking

Background: MOTS-c and Romo1 are mitochondrial peptides that are modulated by oxidative stress. No previous studies have explored circulating levels of MOTS-c in patients with chronic obstructive pulmonary disease (COPD)., Methods: We enrolled 142 patients with stable COPD and 47 smokers with normal lung function in an observational cross-sectional study. We assessed serum levels of both MOTS-c and Romo1 and associated these findings with clinical characteristics of COPD., Results: Compared with smokers with normal lung function, patients with COPD had lower levels of MOTS-c ( p = 0.02) and higher levels of Romo1 ( p = 0.01). A multivariate logistic regression analysis revealed that above-median MOTS-c levels were positively associated with Romo1 levels (OR 1.075, 95% CI 1.005-1.150, p = 0.036), but no association was found with other COPD characteristics. Below-median levels of circulating MOTS-c were associated with oxygen desaturation (OR 3.25 95% CI 1.456-8.522, p = 0.005) and walking <350 meters (OR 3.246 95% CI 1.229-8.577, p = 0.018) in six-minute walk test. Above-median levels of Romo1 were positively associated with current smoking (OR 2.756, 95% CI 1.133-6.704, p = 0.025) and negatively associated with baseline oxygen saturation (OR 0.776 95% CI 0.641-0.939, p = 0.009)., Conclusions: Reduced levels of circulating MOTS-c and increased levels of Romo1 were detected in patients diagnosed with COPD. Low levels of MOTS-c were associated with oxygen desaturation and poorer exercise capacity using 6 min walk test. Romo1 was associated with current smoking and baseline oxygen saturation., Trial Registration: www.clinicaltrials.gov; No.: NCT04449419; URL: www.clinicaltrials.gov. Date of registration: June 26, 2020., Competing Interests: CA has received speaker or consulting fees from Boehringer Ingelheim, Pfizer, AstraZeneca, Novartis, Chiesi, Faes Farma, Esteve, and GSK. CC has received speaker or consulting fees from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, and research grants from GSK, Menarini, and AstraZeneca. DF-P has received speaker or consulting fees from Chiesi and GSK. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Amado, Martín-Audera, Agüero, Lavín, Guerra, Boucle, Ferrer-Pargada, Berja, Martín, Casanova and García-Unzueta.)

Background: Chronic obstructive pulmonary disease (COPD) exacerbation (ECOPD) alters the natural course of the disease. To date, only C-reactive protein has been used as a biomarker in ECOPD, but it has important limitations. The mitochondria release peptides (Humanin (HN), FGF-21, GDF-15, MOTS-c and Romo1) under certain metabolic conditions. Here, we aimed to evaluate the pathophysiologic, diagnostic and prognostic value of measuring serum mitochondrial peptides at hospital admission in patients with ECOPD., Methods: A total of 51 consecutive patients admitted to our hospital for ECOPD were included and followed for 1 year; in addition, 160 participants with stable COPD from our out-patient clinic were recruited as controls., Results: Serum FGF-21 ( p < .001), MOTS-c ( p < .001) and Romo1 ( p = .002) levels were lower, and GDF-15 ( p < .001) levels were higher, in patients with ECOPD than stable COPD, but no differences were found in HN. In receiver operating characteristic analysis, MOTS-c (AUC 0.744, 95% CI 0.679-0.802, p < .001) and GDF-15 (AUC 0.735, 95% CI 0.670-0.793, p < .001) had the best diagnostic power for ECOPD, with a diagnostic accuracy similar to that of C-RP (AUC 0.796 95% IC 0.735-0.848, p < .001). FGF-21 (AUC 0.700, 95% CI 0.633-0.761, p < .001) and Romo1 (AUC 0.645 95% CI 0.573-0.712, p = .001) had lower diagnostic accuracy. HN levels did not differentiate patients with ECOPD versus stable COPD ( p = .557). In Cox regression analysis, HN (HR 2.661, CI95% 1.009-7.016, p = .048) and MOTS-c (HR 3.441, CI95% 1.252-9.297, p = .016) levels exceeding mean levels were independent risk factors for re-admission., Conclusions: Most mitochondrial peptides are altered in ECOPD, as compared with stable COPD. MOTS-c and GDF15 levels have a diagnostic accuracy similar to C-RP for ECOPD. HN and MOTS-c independently predict future re-hospitalization., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Partially funded by GSK. Carlos Amado has received speaker or consulting fees from Boehringer Ingelheim, Pfizer, AstraZeneca, Novartis, Chiesi, Faes Farma, Esteve and GSK. Diego Ferrer has received speaker or consulting fees from Chiesi and GSK. The rest of the authors do not have any conflict of interest.

Background: The 2-dimensional, 4-quadrant 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD A-D assessment tool (GOLD 2017 ) does not include lung function variables to classify patients into different risk groups. The previous 2011 tool (GOLD 2011 ) classified cases in the upper-quadrants (higher risk groups) regardless of whether they had a history of exacerbations or worse lung function. We hypothesized that a modified, three-dimensional classification (GOLD 3D ) that separately includes assessment of lung function and exacerbations history would improve the ability to predict adverse events., Methods: A total of 1303 COPD patients were included in a historical cohort study. The ability of GOLD 3D to predict outcomes (all-cause death and hospitalizations due to severe exacerbation) was compared with GOLD 2017 and GOLD 2011 ., Results: Mean follow-up was 45.0 ± 28.0 months. Two hundred and twenty-eight patients (17.5%) died and 337 (25.9%) subjects suffered at least a severe exacerbation that required hospital admission. The area under the receiver-operating characteristics curve for mortality prediction was slightly but significantly higher for GOLD 3D than for GOLD 2011 . The area under the curve for prediction of severe exacerbations was significantly higher for GOLD 3D than for GOLD 2011 and GOLD 2017 . A worse ventilatory obstruction was associated in most cases with a higher mortality risk and a higher exacerbation risk for the GOLD2017 A-D groups., Conclusions: The proposed GOLD 3D classification system upgrades the previous ones, and is advantageous in predicting future adverse events., Competing Interests: Disclosure of interest The authors report no conflict of interest., (Copyright © 2021 SPLF and Elsevier Masson SAS. All rights reserved.)