Ionomycin suppresses tumor cell growth by disrupting mitochondrial transcription

Recent studies have identified allosteric inhibitors of the mitochondrial RNA polymerase (POLRMT), such as IMT1 and IMT1B, as potential anticancer agents. Here, we report that Ionomycin, a selective Ca²⁺ ionophore that is commonly used together with phorbol 12-myristate 13-acetate (PMA) to activate T cells, also disrupts mitochondrial transcription.

RNA sequencing analysis showed that Ionomycin treatment markedly reduced transcription of mitochondrial DNA (mtDNA). To confirm this effect, we measured both total RNA and Nascent (newly transcribed) RNA in four tumor cell lines (Jurkat, HeLa, H441, and THP1), finding consistent suppression of mitochondrial gene expression. Nascent RNA sequencing further validated these results.Functionally, this transcriptional repression impaired OXPHOS activity, leading to reduced energy production.