Mitochondria contain a 16-kb double stranded DNA genome encoding 13 proteins essential for respiration, but the mechanisms regulating transcription and their potential role in cancer remain elusive. Although methyl-CpG-binding domain (MBD) proteins are essential for nuclear transcription, their role in mitochondrial DNA (mtDNA) transcription is unknown. Here we report that the MBD2c splicing variant translocates into mitochondria to mediate mtDNA transcription and increase mitochondrial respiration in triple-negative breast cancer (TNBC) cells. In particular, MBD2c binds the noncoding region in mtDNA and interacts with SIRT3, which in turn deacetylates and activates TFAM, a primary mitochondrial transcription factor, leading to enhanced mtDNA transcription. Furthermore, MBD2c recovered the decreased mitochondrial gene expression caused by the DNA synthesis inhibitor cisplatin, preserving mitochondrial respiration and consequently enhancing drug resistance and proliferation in TNBC cells. These data collectively demonstrate that MBD2c positively regulates mtDNA transcription, thus connecting epigenetic regulation by deacetylation with cancer cell metabolism, suggesting druggable targets to overcome resistance.

线粒体包含一个 16 kb 的双链 DNA 基因组，编码 13 种对呼吸至关重要的蛋白质，但调节转录的机制及其在癌症中的潜在作用仍然难以捉摸。尽管甲基 CpG 结合结构域 （MBD） 蛋白对核转录至关重要，但它们在线粒体 DNA （mtDNA） 转录中的作用尚不清楚。在这里，我们报道了 MBD2c 剪接变体易位到线粒体中，以介导三阴性乳腺癌 （TNBC） 细胞中的 mtDNA 转录并增加线粒体呼吸。特别是，MBD2c 结合 mtDNA 中的非编码区并与 SIRT3 相互作用，后者反过来使 TFAM（一种主要的线粒体转录因子）脱乙酰并激活，从而增强 mtDNA 转录。此外，MBD2c 恢复了 DNA 合成抑制剂顺铂引起的线粒体基因表达降低，保留了线粒体呼吸，从而增强了 TNBC 细胞的耐药性和增殖。这些数据共同表明 MBD2c 正向调节 mtDNA 转录，从而将脱乙酰化的表观遗传调控与癌细胞代谢联系起来，表明可成药靶点可以克服耐药性。