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CPT1A-mediated MFF succinylation promotes stemness maintenance in ovarian cancer stem cells by enhancing mitochondria-associated membranes formation

ABSTRACT: Cancer stem cells (CSCs) are key players in cancer progression, immune evasion, drug resistance, and recurrence, particularly in ovarian cancer. Mitochondria-associated membranes (MAMs) are dynamic structures linking mitochondria and the endoplasmic reticulum, essential for cellular processes. Whether MAMs supports CSCs and the underlying mechanisms remain largely unknown. Here, we unveil that CPT1A is highly expressed in ovarian cancer stem cells (OCSCs) and is essential for stemness maintenance. CPT1A facilitates stemness maintenance by regulating lipid desaturation in ovarian cancer. Further studies confirmed that CPT1A enhances SREBP1 cleavage and nuclear translocation, thereby upregulating SCD1 expression and promoting lipid desaturation in OCSCs. Furthermore, MAMs are found to be critical for SREBP1 activation. Mechanistic studies have shown that CPT1A promotes mitochondrial fission factor (MFF) succinylation (succK-MFF) through its lysine succinyltransferase (LSTase) activity, with succK-MFF being crucial for MAMs formation and SREBP1 activation. Additionally, inhibiting the LSTase activity of CPT1A with Glyburide reduced OCSCs' stemness and enhanced cisplatin's anti-tumor effects against ovarian cancer both in vitro and in vivo. Together, our studies reveal the importance of CPT1A's LSTase activity in MAMs formation and OCSCs' stemness maintenance, providing potential targets and therapeutic strategies for ovarian cancer treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273383 | GEO | 2024/08/26

REPOSITORIES: GEO

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Project description:Elevated mitochondrial biogenesis and metabolism represent key features of breast cancer stem cells (CSCs), whose propagation is conducive to disease onset and progression. Therefore, interfering with mitochondria biology and function may be regarded as a useful approach to eradicate CSCs. Here, we used the breast cancer cell line MCF7 as a model system to interrogate how mitochondrial fission contributes to the development of mitochondrial dysfunction toward the inhibition of metabolic flux and stemness. We generated an isogenic MCF-7 cell line transduced with Mitochondrial Fission Factor (MCF7-MFF), which is primarily involved in mitochondrial fission. We evaluated the biochemical, molecular and functional properties of MCF7-MFF cells, as compared to control MCF7 cells transduced with the empty vector (MCF7-Control). We observed that MFF over-expression reduces both mitochondrial mass and activity, as evaluated using the mitochondrial probes MitroTracker Red and MitoTracker Orange, respectively. The analysis of metabolic flux using the Seahorse XFe96 revealed the inhibition of OXPHOS and glycolysis in MCF7-MFF cells, suggesting that increased mitochondrial fission may impair the biochemical properties of these organelles. Notably, CSCs activity, assessed by 3D-tumorsphere assays, was reduced in MCF7-MFF cells. A similar trend was observed for the activity of ALDH, a well-established marker of stemness. We conclude that enhanced mitochondrial fission may compromise CSCs propagation, through the impairment of mitochondrial function, possibly leading to a quiescent cell phenotype. Unbiased proteomic analysis revealed that proteins involved in mitochondrial dysfunction, oxidative stress-response, fatty acid metabolism and hypoxia signaling are among the most highly up-regulated in MCF7-MFF cells. Of note, integrated analysis of top regulatory networks obtained from unbiased proteomics in MCF7-MFF cells predicts that this cell phenotype activates signaling systems and effectors involved in the inhibition of cell survival and adhesion, together with the activation of specific breast cancer cell death programs. Overall, our study shows that unbalanced and abnormal activation of mitochondrial fission may drive the impairment of mitochondrial metabolic function, leading to inhibition of CSC propagation, and the activation of quiescence programs. Exploiting the potential of mitochondria to control pivotal events in tumor biology may, therefore, represent a useful tool to prevent disease progression.

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CPT1A-mediated MFF succinylation promotes stemness maintenance in ovarian cancer stem cells by enhancing mitochondria-associated membranes formation

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