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MEX3A control of mitochondrial fitness is essential for ovarian clear cell carcinoma tumorigenesis and liver metastasis

ABSTRACT: Ovarian cancer (OC) is highly metastatic and chemoresistant. Due to heterogeneity among OC subtypes, the mechanisms underlying OC malignancy and metastasis remain largely unknown. Ovarian clear cell carcinoma (OCCC) accounts for 5-25% of OC and its incidence rate is rising. Liver metastasis is particularly high in OCCC patients and leads to significantly reduced median survival. Why OCCC metastasizes to liver at such high frequency remains elusive. We previously identified MEX3A as a key factor that promotes OCCC tumorigenesis in part by circumventing p53-mediated ferroptosis. Here, we report that MEX3A control of mitochondrial fitness, which occurs independently of p53, is essential for OCCC primary tumor growth and liver metastasis. MEX3A depletion resulted in chronic mitochondrial fragmentation and accumulation of non-functional mitochondria. MEX3A-depleted cells had decreased mitochondrial membrane potential, increased superoxide and decreased NAD+/NADH ratio, resulting in inhibition of oxidative phosphorylation (OXPHOS) and decreased ATP levels. In an environment enriched with mitophagy stressors, such as the liver, MEX3A-depleted OCCC cells had greatly reduced survival due to failure to recover from mitophagy. Consistent with these observations, MEX3A knockdown greatly reduced liver metastasis. Together, these data demonstrate that MEX3A-mediated mitochondrial fitness is a major factor underlying its p53-independent promotion of OCCC tumorigenesis and liver metastasis. Thus, targeting MEX3A will be a promising strategy to inhibit OCCC progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310582 | GEO | 2026/03/31

REPOSITORIES: GEO

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Project description:Background: Carotid artery atherosclerosis (CAS), has exhibited an increasing incidence in recent years. Although Huaban Tongmai decoction (HBTMD) shows considerable therapeutic potential against CAS, the specific molecular mechanisms of its action remain incompletely defined.Purpose: This study aimed to explore and clarify the underlying mechanisms through which HBTMD mitigates CAS.Methods: The components of HBTMD were analyzed using UHPLC-MS/MS. An ApoE-/- mouse model of CAS was established in vivo by combining a high-fat diet with carotid artery ligation. The extent of AS in carotid arteries was assessed using hematoxylin-eosin (HE) and Oil Red O (ORO) staining. Integrated proteomics and metabolomics analyses were conducted to screen key differentially expressed proteins (DEPs) and metabolites associated with HBTMD intervention. Potential targets and pathways were systematically explored. Transmission electron microscopy (TEM), quantitative real-time PCR (qRT-PCR), Western blot (WB), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and immunofluorescence (IF) were performed to evaluate markers related to ferroptosis and mitophagy, thus validating key pathway targets. In vitro, a cellular model of AS was established by inducing human umbilical vein endothelial cells (HUVECs) with ox-LDL. Ferroptosis and mitophagy levels were assessed using TEM, qRT-PCR, WB, ELISA, and reactive oxygen species (ROS) detection. Key pathway targets were further verified. Additionally, the ferroptosis inhibitor Ferrostatin-1 (Fer-1), the mitophagy inhibitor (Mdivi-1), and p53-specific small interfering RNA (siRNA) were employed to further clarify the mechanism of HBTMD.Results: A comprehensive UHPLC-MS/MS analysis identified 684 chemical constituents within HBTMD. In vivo studies indicated significant reductions in both lipid accumulation and atherosclerotic plaque areas following HBTMD treatment. Integrated analyses involving proteomics and metabolomics suggested that the therapeutic efficacy of HBTMD might involve modulation of autophagy and ferroptosis pathways. Additional validations through in vitro and in vivo studies demonstrated that HBTMD administration effectively improved mitochondrial structural integrity, decreased the secretion of inflammatory cytokines, and inhibited ferroptosis. Furthermore, HBTMD decreased ROS levels and enhanced mitophagy activity, an effect partially reversed by the mitochondrial division inhibitor Mdivi-1.In vitro, knockdown of the p53 gene did not further enhance the regulatory effects of HBTMD on ferroptosis- and mitophagy-related proteins.Conclusion: This study provides the first evidence that the anti-atherosclerotic effect of HBTMD occurs via the regulation of the p53-Parkin signaling pathway, thereby enhancing mitophagy and suppressing ferroptosis.

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MEX3A control of mitochondrial fitness is essential for ovarian clear cell carcinoma tumorigenesis and liver metastasis

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