Relation of mitochondrial DNA copy number and variants with the clinical characteristics of polycystic ovary syndrome

Mounting evidences suggests mitochondrial dysfunction as a novel contributor in the pathogenesis of PCOS. Herein, we analyzed mtDNA copy number, a biomarker of mitochondrial function in women with PCOS and non-PCOS participants and study its correlation with their clinical characteristics. In this study, we further analyzed association of 383 mtDNA variants, as reported previously by us, with characteristic traits of PCOS and perform structural analysis of mutated protein. Our results indicate relative mitochondrial DNA (mtDNA) copy number to be significantly reduced in women with PCOS compared to non-PCOS group and significantly inversely related to waist to hip ratio (WHR), triglycerides and positively related to high density lipoprotein-cholesterol (HDL-C). After adjustment of the age in the PCOS group, significantly negative correlation of mtDNA copy number with WHR was observed. Unsupervised hierarchical clustering analysis revealed rare, low heteroplasmic mtDNA variants such as 12556G, 1488T, 9200G, 9670G, 3308G, 14480G, 15914T and 5426G to be strongly associated with PCOS related traits. Among these variants, variant 12256G in ND5 gene affected both the flexibility and overall stability of the protein structure. This study is first to reveal significant correlation of mtDNA copy number with WHR in women with PCOS indicating link between mitochondrial dysfunction with central obesity in PCOS. we also first time showed association of rare mtDNA variants with characteristics traits of PCOS highlighting the clinical significance of rare mtDNA variants, which may cumulatively act as early predictors of risk of PCOS and its related comorbidities which may help in the management of PCOS.