Jawla Neha, Kar Raunak, Patil Veena S, Arimbasseri G Aneeshkumar
Molecular Genetics Laboratory, National Institute of Immunology, New Delhi, India.
Immuno Genomics Laboratory, National Institute of Immunology, New Delhi, India.
Immunology. 2025 Jan;174(1):73-91. doi: 10.1111/imm.13860. Epub 2024 Sep 12.
Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well-established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear-encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2-deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.
线粒体翻译对于维持线粒体功能和能量产生至关重要。与线粒体翻译相关的基因突变会导致多种发育障碍，并且在许多此类患者中观察到免疫功能障碍。除了基因突变外，几种靶向细菌核糖体的抗生素已被证实可抑制线粒体翻译。然而，此类抗生素对不同免疫细胞的影响尚未完全了解。在此，我们探讨了线粒体翻译抑制对小鼠和人类辅助性T细胞（Th）不同亚群的差异影响。线粒体翻译的抑制降低了线粒体编码的电子传递链亚基的水平，而不影响其核编码的对应亚基。结果，线粒体氧消耗显著降低，但线粒体质量未受影响。最重要的是，我们表明线粒体翻译的抑制诱导了细胞凋亡，特别是在Th2细胞中。这种凋亡增加与凋亡内在途径的两种激活剂Bim和Puma的更高表达相关。我们提出，Th1和Th2细胞对线粒体翻译抑制敏感性的这种差异反映了这些亚群的内在代谢需求。虽然Th1和Th2细胞表现出相似水平的氧化磷酸化，但Th1细胞比Th2细胞表现出更高水平的有氧糖酵解。此外，Th1细胞对糖酵解抑制更敏感，而诱导Th2谱系细胞死亡需要更高浓度的糖酵解抑制剂2-脱氧葡萄糖。这些观察结果表明，Th1和Th2谱系分化过程中底物利用代谢途径的选择是一个跨物种保守的基本过程。
