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In this context, this study aimed to investigate the effects of high copper levels on cell viability, mitochondrial physiology, PINK1 content, and the expression of PGC-1\u03b1 and TFAM in distinct glioma cell lines, mainly considering the heterogeneity of tumoral cells. GBM-1, U-87 MG, and C6 cells CuSO\n                    <jats:sub>4<\/jats:sub>\n                    exposure (0\u20131200\u00a0\u00b5M) was performed for 24\u00a0h, and cell viability was assessed using the MTT reduction and Neutral Red (NR) assays. NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase activities, and the mitochondrial membrane potential (\u0394\u03a8m) were measured to analyze mitochondrial physiology. PINK1 was evaluated by immunofluorescence, while PGC-1\u03b1 and TFAM expression were assessed by real-time RT-PCR in U-87 MG and C6 cells. Copper exposure reduced cell viability in the cell lines (MTT and NR), except in U-87 MG with the NR assay. High copper levels decreased succinate dehydrogenase activity in GBM-1, U-87 MG, and C6 cells. Cytochrome c oxidase activity was decreased in the C6 cell line. Moreover, reductions in \u0394\u03a8m and increases in PINK1 immunostaining were observed across the three cell lines. Finally, an increase in PGC-1\u03b1 mRNA was observed in C6 cells, and TFAM expression has risen in U-87 MG. In conclusion, high copper levels decrease glioma cell viability in vitro, and mitochondrial dysfunction contributes to this effect, resulting in PINK1 and TFAM or PGC-1\u03b1 increase as compensatory mechanisms to copper cytotoxicity.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\n                    Exposure to high copper levels (CuSO\n                    <jats:sub>4<\/jats:sub>\n                    ) promotes mitochondrial dysfunction in glioma cells, including loss of mitochondrial membrane potential (\u0394\u03a8m), and impairment of respiratory chain activity, besides increasing PINK1. Indeed, U-87 MG cells display increased TFAM expression, and C6 cells exhibit increased PGC-1\u03b1 expression, consistent with activation of mitochondrial biogenesis pathways. 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