Dataset Information

Endometrium and endometriosis tissue mitochondrial energy metabolism in a nonhuman primate model.

ABSTRACT:

Background

Endometriosis is the growth of uterine lining (endometrium) outside of the uterus. In other chronic inflammatory diseases, mitochondrial dysfunction is suspected of playing a role in disease pathogenesis. However, little is known about endometriosis mitochondrial function or its effects on tissue metabolism. The objectives of this study were to analyze mitochondrial function in nonhuman primate (NHP) endometrium and endometriosis tissue and to identify the metabolic features of these tissues that may contribute to disease.

Methods

Mitochondrial function in endometriosis tissue and endometrium was measured using mitochondrial respirometry analysis to determine if changes in oxidative phosphorylation exist in endometrium and endometriosis tissue compared to control endometrium from clinically healthy NHPs. Targeted metabolomics and multidimensional statistical analysis were applied to quantify key metabolites in energy and amino acid biosynthesis pathways.

Results

Mitochondrial respirometry assays showed endometrium from NHPs with endometriosis had reduced complex II-mediated oxygen consumption rates (OCR) across all energy states (basal, p =?0.01; state 3, p =?0.02; state 3u, p =?0.04; state 4o, p =?0.008) and endometriosis tissue had reduced state 3, complex I-mediated OCR (p =?0.02) and respiratory control rates (p =?0.01) compared to normal endometrium. Targeted metabolomics performed on tissue revealed carnitine (p =?0.001), creatine phosphate (p =?0.01), NADH (p =?0.0001), FAD (p =?0.001), tryptophan (p =?0.0009), and malic acid (p =?0.005) were decreased in endometriosis tissue compared to normal endometrium samples. FAD (p =?0.004), tryptophan (p =?0.0004) and malic acid (p =?0.03) were significantly decreased in endometrium from NHPs with endometriosis compared to normal endometrium. Significant metabolites identified in endometriosis and endometrium samples from animals with endometriosis were part of amino acid biosynthesis or energy metabolism pathways.

Conclusions

Here, endometrial mitochondrial energy production and metabolism were decreased in endometrium and endometriosis tissue. Decreased mitochondrial energy production may be due to oxidative stress-induced damage to mitochondrial DNA or membranes, a shift in cell metabolism, or decreased energy substrate; however, the exact cause remains unknown. Additional research is needed to determine the implications of reduced mitochondrial energy production and metabolism on endometriosis and endometrium.

SUBMITTER: Atkins HM

PROVIDER: S-EPMC6708555 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Endometrium and endometriosis tissue mitochondrial energy metabolism in a nonhuman primate model.

Atkins Hannah M HM Bharadwaj Manish S MS O'Brien Cox Anderson A Furdui Cristina M CM Appt Susan E SE Caudell David L DL

Reproductive biology and endocrinology : RB&E 20190824 1

<h4>Background</h4>Endometriosis is the growth of uterine lining (endometrium) outside of the uterus. In other chronic inflammatory diseases, mitochondrial dysfunction is suspected of playing a role in disease pathogenesis. However, little is known about endometriosis mitochondrial function or its effects on tissue metabolism. The objectives of this study were to analyze mitochondrial function in nonhuman primate (NHP) endometrium and endometriosis tissue and to identify the metabolic features o ...[more]

PMID: 31445519

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Project description:Study questionIs it possible to establish a genetically engineered mouse model (GEMM) of endometriosis that mimics the natural spread of invasive endometrium?Summary answerEndometriosis occurs in an ARID1A (AT-rich interactive domain-containing protein 1A) and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutant GEMM of endometrial dysfunction following salpingectomy.What is known alreadyAlthough mouse models of endometriosis have long been established, most models rely on intraperitoneal injection of uterine fragments, steroid hormone treatments or the use of immune-compromised mice.Study design, size, durationMice harboring the lactotransferrin-Cre (LtfCre0/+), Arid1afl, (Gt)R26Pik3ca*H1047R and (Gt)R26mTmG alleles were subject to unilateral salpingectomies at 6 weeks of age. Control (n = 9), LtfCre0/+; (Gt)R26Pik3ca*H1047R; Arid1afl/+ (n = 8) and LtfCre0/+; (Gt)R26Pik3ca*H1047R; Arid1afl/fl (n = 9) were used for the study. The (Gt)R26mTmG allele was used for the purpose of fluorescent lineage tracing of endometrial epithelium. LtfCre0/+; (Gt)R26mTmG (n = 3) and LtfCre0/+; (Gt)R26Pik3ca*H1047R/mTmG; Arid1afl/fl (n = 4) were used for this purpose. Mice were followed until the endpoint of vaginal bleeding at an average time of 17 weeks of age.Participants/materials, setting, methodsAt 6 weeks of age, mice were subjected to salpingectomy surgery. Mice were followed until the time point of vaginal bleeding (average 17 weeks), or aged for 1 year in the case of control mice. At time of sacrifice, endometriotic lesions, ovaries and uterus were collected for the purpose of histochemical and immunohistochemical analyses. Samples were analyzed for markers of the endometriotic tissue and other relevant biomarkers.Main results and the role of chanceFollowing salpingectomy, LtfCre0/+; (Gt)R26Pik3ca*H1047R/mTmG; Arid1afl/fl mice developed endometriotic lesions, including lesions on the ovary, omentum and abdominal wall. Epithelial glands within lesions were negative for ARID1A and positive for phospho-S6 staining, indicating ARID1A-PIK3CA co-mutation status, and expressed EGFP (enhanced green fluorescent protein), indicating endometrial origins.Large-scale dataN/A.Limitations, reasons for cautionLtfCre0/+; (Gt)R26Pik3ca*H1047R; Arid1afl/fl mice develop vaginal bleeding as a result of endometrial dysfunction at an average age of 17 weeks and must be sacrificed. Furthermore, while this model mimics the natural spread of endometriotic tissue directly from the uterus to the peritoneum, the data presented do not reject current hypotheses on endometriosis pathogenesis.Wider implications of the findingsThe idea that endometriosis is the result of abnormal endometrial tissue colonizing the peritoneum via retrograde menstruation has gained widespread support over the past century. However, most models of endometriosis take for granted this possibility, relying on the surgical removal of bulk uterine tissue and subsequent transplantation into the peritoneum. Growing evidence suggests that somatic mutations in ARID1A and PIK3CA are present in the endometrial epithelium. The establishment of a GEMM which mimics the natural spread of endometrium and subsequent lesion formation supports the hypothesis that endometriosis is derived from mutant endometrial epithelium with invasive properties.Study funding/competing interest(s)This research was supported by the American Cancer Society PF-17-163-02-DDC (M.R.W.), the Mary Kay Foundation 026-16 (R.L.C.) and the Ovarian Cancer Research Fund Alliance 457446 (R.L.C.). The authors declare no competing interests.

Dataset Information

Endometrium and endometriosis tissue mitochondrial energy metabolism in a nonhuman primate model.

Background

Methods

Results

Conclusions

Publications

Endometrium and endometriosis tissue mitochondrial energy metabolism in a nonhuman primate model.

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