BACKGROUNDMitochondrial dysfunction, a proposed mechanism of
chronic obstructive pulmonary disease (
COPD) pathogenesis, is associated with the leakage of
mitochondrial DNA (
mtDNA), which may be detected extracellularly in various bodily fluids. Despite evidence for the increased prevalence of
chronic kidney disease in
COPD subjects and for
mitochondrial dysfunction in the kidneys of murine
COPD models, whether urine
mtDNA (u-
mtDNA) associates with measures of disease severity in
COPD is unknown.METHODSCell-free u-
mtDNA, defined as copy number of mitochondrially encoded
NADH dehydrogenase-1 (MTND1) gene, was measured by quantitative PCR and normalized to urine
creatinine in cell-free urine samples from participants in the Subpopulations and Intermediate Outcome Measures in
COPD Study (SPIROMICS) cohort. Urine
albumin/
creatinine ratios (UACR) were measured in the same samples. Associations between u-
mtDNA, UACR, and clinical disease parameters - including FEV1 % predicted, clinical measures of exercise tolerance, respiratory symptom burden, and chest CT measures of lung structure - were examined.RESULTSU-
mtDNA and UACR levels were measured in never smokers (n = 64), smokers without airflow obstruction (n = 109), participants with mild/moderate
COPD (n = 142), and participants with severe
COPD (n = 168). U-
mtDNA was associated with increased respiratory symptom burden, especially among smokers without
COPD. Significant sex differences in u-
mtDNA levels were observed, with females having higher u-
mtDNA levels across all study subgroups. U-
mtDNA associated with worse spirometry and CT
emphysema in males only and with worse respiratory symptoms in females only. Similar associations were not found with UACR.CONCLUSIONU-
mtDNA levels may help to identify distinct clinical phenotypes and underlying pathobiological differences in males versus females with
COPD.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov ( NCT01969344).FUNDINGUS NIH, National Heart, Lung and Blood Institute, supplemented by contributions made through the Foundation for the NIH and the
COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon
Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici S.p.A., Forest Research Institute Inc., GlaxoSmithKline, Grifols
Therapeutics Inc., Ikaria Inc., Novartis Pharmaceuticals Corporation, Nycomed GmbH, ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, Sunovion, Takeda Pharmaceutical Company, and Theravance Biopharma and Mylan.