Accumulation of cholesterol, cortisol, and glutathione in mitochondria as a marker of metabolic adaptation in serous and clear cell endometrial carcinoma.

Abstract

5617 Background: Aggressive endometrial carcinoma subtypes, such as serous (USC) and clear cell (CCC) carcinomas, are characterized by distinct cellular metabolism and dysregulation. Altered homeostasis of metabolites and hormones within mitochondria serves as a molecular driver of metabolic reprogramming in cancer cells. Excess mitochondrial cholesterol can induce oxidative stress, whereas glutathione provides antioxidant defense. Cortisol levels are capable of modulating organelle function. The aim of this study was to evaluate the levels of cholesterol, cortisol, and glutathione in mitochondria isolated from serous and clear cell endometrial carcinomas to characterize the metabolic profile of tumor cells. Methods: The study was conducted on mitochondria isolated from tumor tissue of 41 patients with USC (n=21) and CCC (n=20), stage III–IV, histological grade G3; the mean patient age was 59.6±6.7 years. Mitochondria isolated from normal endometrium (n=20) obtained during hysterectomies for uterine leiomyoma (mean age 57.8±8.2 years) served as controls. Cortisol, cholesterol, and glutathione concentrations in the mitochondrial fraction were determined by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using parametric and nonparametric tests with adjustments for multiple comparisons. Results: A significant increase in cholesterol levels was observed in mitochondria from these rare endometrial carcinoma subtypes: 2.1-fold in USC and 1.9-fold in CCC compared with normal endometrium. Cortisol content was elevated by 2.1- and 2.5-fold, respectively. Mitochondrial glutathione concentration was also increased: 2.4-fold in USC and 1.9-fold in CCC. Conclusions: The data reveal a universal mechanism of metabolic adaptation in serous and clear cell endometrial carcinomas, characterized by a unified mitochondrial metabolic profile featuring co-accumulation of cholesterol, cortisol, and glutathione. Elevated cholesterol generates a pro-apoptotic signal, which is counterbalanced by increased glutathione levels to maintain redox homeostasis. The concurrent rise in cortisol indicates the engagement of mitochondrial stress-response pathways. This constellation of alterations reflects fundamental reprogramming of cellular homeostasis in aggressive endometrial cancers and may be considered a potential target for mitochondrial-directed therapy.