Mitochondrial connexin 43 modulates metabolic stress adaptation in glioma cell lines

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Connexin 43 (CX43) is a hemichannel (HC)- and gap junction (GJ)-forming protein that mediates the exchange of small molecules between the intracellular and extracellular environments, as well as intercellular communication. In addition to this canonical role, recent studies have shown that its functions range from transcriptional regulation to intracellular homeostasis. The ability of CX43 to translocate into mitochondria suggests its involvement in energy metabolism. However, the functions of mitochondrial CX43 (mt-CX43) in neural cells remain unexplored. Our study investigated the expression and localisation of mt-CX43 through western blot and immunofluorescence analyses in four immortalised human glioma cell lines: T98-G, A-172, CCF-STTG1, and U-87 MG. Additionally, targeted metabolomic analysis was conducted to assess changes in key metabolic pathways. Basal CX43 expression and extracellular stress factors, particularly cell density and extracellular pH fluctuations, significantly modulated the mitochondrial localisation of CX43. Inhibition of the heat shock protein 90 (HSP90) chaperone system by geldanamycin (GA) resulted in a marked reduction in mt-CX43, suggesting an import mechanism involving HSP90 and the translocase of the outer membrane (TOM) complex. In addition, the assessment of key metabolites revealed increased purine biosynthesis in T98-G cells exposed to GA treatment, characterised by lower basal CX43 expression and reduced mt-CX43 levels under stress conditions. Conversely, U-87 MG cells exhibited a stable NAD+/NADH ratio and a significant increase in NADH levels, indicating a metabolic shift towards a more resilient state. Our results suggest that mt-CX43 serves as a multifunctional regulator of metabolic adaptation and stress response in glioma cell lines. Our results extend the role of mt-CX43 as an essential factor in cellular metabolic plasticity, providing new insights into the modulation of metabolic imbalances and mitochondrial dysfunction. Connexin 43 (CX43) is a multifunctional protein known for its canonical role in forming hemichannels and gap junctions, which mediate the exchange of signals and small molecules. Although this pore-forming function occurs primarily at the plasma membrane, CX43 is also localised within mitochondria, suggesting a role in cellular adaptation to energy demands and environmental stress. In this study, we investigated the role of mitochondrial CX43 (mt-CX43) in glioma cell lines. We found that mt-CX43 levels vary depending on cell density and extracellular pH. Furthermore, the import of CX43 into mitochondria requires a transport system involving heat shock protein 90 (HSP90). Inhibition of this system with geldanamycin caused a consistent reduction in mt-CX43, which was associated with alterations in mitochondrial structure and metabolic pathways, including purine metabolism and NADH turnover. Our findings suggest that mt-CX43 is required for cellular adaptation to metabolic stress and that modulating mt-CX43 may represent a novel strategy to disrupt tumour survival mechanisms and improve glioma treatment.

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