Yardeni Tal, Olali Arnold Z, Chen Hsiao-Wen, Wang Liqing, Haltom Jeffrey A, Zenab Angi, Morrow Ryan, Butic Arrienne, Murdock Deborah G, Waymire Katrina G, MacGregor Grant R, Boursi Ben, Beier Ulf H, Hancock Wayne W, Wallace Douglas C
Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Bert Strassburger Metabolic Center for Preventive Medicine, Sheba Medical Center, Tel Hashomer 5262000, Israel.
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2417252121. doi: 10.1073/pnas.2417252121. Epub 2025 Jan 3.
Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA-cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, and , where mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mice exhibited strikingly impaired tumor growth while mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of Teff cells increased mitochondrial gene expression while activation of Treg cells impaired mitochondrial gene expression and resulted in Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti-PD-L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction.
线粒体DNA（mtDNA）具有高度多态性，宿主mtDNA变异与癌症严重程度改变有关。为了确定这种mtDNA与癌症关联的基础，我们分析了具有C57BL/6J（B6）细胞核但有两种天然存在的mtDNA谱系的同核异质小鼠，其中，线粒体产生更多氧化磷酸化（OXPHOS）衍生的活性氧（mROS）。在心脏移植模型中，Foxp3 +调节性T（Treg）细胞支持长期同种异体移植存活，而Treg细胞未能抑制宿主效应T（Teff）细胞，导致急性排斥反应。当受到黑色素瘤或结肠癌细胞攻击时，小鼠的肿瘤生长明显受损，而小鼠则表现出Treg细胞对Teff细胞的依赖性抑制，并允许肿瘤快速生长。转录分析表明，Teff细胞的激活增加了线粒体基因表达，而Treg细胞的激活则损害了线粒体基因表达，并导致Treg细胞耗竭。在造血细胞中诱导线粒体靶向催化抗氧化剂mCAT，可使移植和肿瘤模型中的Treg功能正常化，表明mROS在促进Treg功能障碍中起关键作用。抗PD-L1疗法并未调节这些效应，这表明调节宿主线粒体功能为增强肿瘤细胞破坏提供了一种独立的方法。
