Mitochondrial Genome Variations in Advanced Stage Endometriosis: A Study in South Indian Population

Abstract

BackgroundEndometriosis is a chronic gynecological benign disease that shares several features similar to malignancy. Mitochondrial DNA (mtDNA) mutations have been reported in all most all types of tumors. However, it is not known as to whether mtDNA mutations are associated with endometriosis.MethodologyWe sequenced the entire mitochondrial genome of analogous ectopic and eutopic endometrial tissues along with blood samples from 32 advanced stage endometriosis patients to analyze the role of somatic and germ-line mtDNA variations in pathogenesis of endometriosis. All ectopic tissues were screened for tumor-specific mtDNA deletions and microsatellite instability (MSI). We also performed mtDNA haplogrouping in 128 patients and 90 controls to identify its possible association with endometriosis risk.Principal FindingsWe identified 51 somatic (novel: 31; reported: 20) and 583 germ-line mtDNA variations (novel: 53; reported: 530) in endometriosis patients. The A13603G, a novel missense mutation which leads to a substitution from serine to glycine at the codon 423 of ND5 gene showed 100% incidence in ectopic tissues. Interestingly, eutopic endometrium and peripheral leukocytes of all the patients showed heteroplasmy (A/G; 40–80%) at this locus, while their ectopic endometrium showed homoplasmic mutant allele (G/G). Superimposition of native and mutant structures of ND5 generated by homology modeling revealed no structural differences. Tumor-specific deletions and MSI were not observed in any of the ectopic tissues. Haplogrouping analysis showed a significant association between haplogroup M5 and endometriosis risk (P: 0.00069) after bonferroni correction.ConclusionsOur findings substantiate the rationale for exploring the mitochondrial genome as a biomarker for the diagnosis of endometriosis.

Endometriosis may be associated with mitochondrial dysfunction in cumulus cells from subjects undergoing in vitro fertilization-intracytoplasmic sperm injection, as reflected by decreased adenosine triphosphate production

“…These data suggest that subjects with endometriosis may have a defect in cumulus cell mitochondrial function, which may contribute to decreased fertilization and implantation rates, as published in a 2002 meta-analysis (2). Although there have been other studies of endometriosis and mitochondrial displacement loop alterations (16), mtDNA deletions (15), and mtDNA polymorphisms (14,17), this is the first study to describe an association between endometriosis and mitochondrial dysfunction in cumulus granulosa cells (GCs). The only other investigation of functional mitochondrial differences with endometriosis showed no statistically significant difference in mitochondrial gene expression of GCs from subjects with severe endometriosis, compared with tubal factor infertility (21).…”

“…Another group (15) has identified a novel 5,335-bp deletion of mtDNA in endometriotic tissue, with more oxidative damage detected in human endometriotic lesions versus control endometrium. Finally, two articles by Govatati et al (16,17) have identified novel alterations in mtDNA in subjects with severe endometriosis.…”

BRCA1 alterations are associated with endometriosis, but BRCA2 alterations show no detectable endometriosis risk: a study in Indian population

“…The causes of endometriosis remain uncertain despite over 100 years of hypothesis-driven research. Earlier, we had demonstrated the correlation between various candidate genes and risk of endometriosis in Indian women [3][4][5][6][7][8][9][10][11][12]. The emerging evidence strongly suggests that the disease has a polygenic and multifactorial basis [13].…”

Genetic, epigenetic and stem cell alterations in endometriosis: new insights and potential therapeutic perspectives

“…As for mtDNA, it has been reported recently that ectopic and eutopic endometrial tissues from patients in a South Indian population affected by advanced stage endometriosis showed several mtDNA variations, including a novel missense mutation in the ND5 gene leading to an amino acid substitution in the corresponding protein, showing a 100 % incidence in ectopic tissues [76]. Another recent association study suggests that the mtDNA 16189 variant and the combination of mtDNA 16189 and 10398 variants increase susceptibility to endometriosis [77].…”