Mitochondrial 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. Cell-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 FEV 1 % predicted, clinical measures of exercise tolerance, respiratory
symptom burden, and chest CT measures of lung structure — were examined. U-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.
U-mtDNA levels may help to identify distinct clinical phenotypes and underlying pathobiological
differences in males versus females with COPD. This study has been registered at ClinicalTrials.gov
( NCT01969344). US 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. Urine mitochondrial DNA associates with
distinct clinical phenotypes in chronic obstructive pulmonary disease in a large multicenter
cohort, with notable sex differences.