线粒体代谢最近被证明对急性髓细胞白血病（AML）具有关键依赖性。线粒体的形态受到动力蛋白GTP酶调节，这些蛋白驱动对称的融合和裂解力量，使生物能量在细胞环境中始终适应。在这里，我们展示了靶向线粒体融合是AML细胞的新弱点，从患者来源的异种移植（PDX）模型中进行了测试。线粒体融合的遗传缺失型号2（MFN2）或视神经萎缩1（OPA1）的基因表达削弱，或采用OPA1（MYLS22）的药物抗阻，可阻止线粒体融合，并显着具有抗白血病活性，而对体外和体内正常造血细胞影响有限。在机械上，抑制线粒体融合对线粒体呼吸和反应性氧化物产生造成了破坏，导致细胞在G0/G1转换处停滞。这些结果将线粒体融合的抑制作为AML的有前途的治疗方法进行提名。©2023.作者。

Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.© 2023. The Author(s).