Myeloid cell leukemia-1 (Mcl-1) is a structurally and functionally unique anti-apoptotic Bcl-2 protein. While elevated levels of Mcl-1 contribute to tumor cell survival and drug resistance, loss of Mcl-1 in cardiac myocytes leads to rapid mitochondrial dysfunction and heart failure development. Although Mcl-1 is an anti-apoptotic protein, previous studies indicate that its functions extend beyond regulating apoptosis. Mcl-1 is localized to both the mitochondrial outer membrane and matrix. Here, we have identified that Mcl-1 in the outer mitochondrial membrane mediates mitochondrial fission, which is independent of its anti-apoptotic function. We demonstrate that Mcl-1 interacts with Drp1 to promote mitochondrial fission in response to various challenges known to perturb mitochondria morphology. Induction of fission by Mcl-1 reduces nutrient deprivation-induced cell death and the protection is independent of its BH3 domain. Finally, cardiac-specific overexpression of Mcl-1_OM, but not Mcl-1_Matrix, contributes to a shift in the balance towards fission and leads to reduced exercise capacity, suggesting that a pre-existing fragmented mitochondrial network leads to decreased ability to adapt to an acute increase in workload and energy demand. Overall, these findings highlight the importance of Mcl-1 in maintaining mitochondrial health in cells.

髓细胞白血病-1 (Mcl-1) 是一种结构和功能独特的抗凋亡 Bcl-2 蛋白。虽然 Mcl-1 水平升高有助于肿瘤细胞存活和耐药性，但心肌细胞中 Mcl-1 的缺失会导致快速的线粒体功能障碍和心力衰竭的发展。尽管 Mcl-1 是一种抗细胞凋亡蛋白，但先前的研究表明其功能超出了调节细胞凋亡的范围。Mcl-1 定位于线粒体外膜和基质。在这里，我们已经确定线粒体外膜中的 Mcl-1 介导线粒体裂变，这与其抗凋亡功能无关。我们证明 Mcl-1 与 Drp1 相互作用以促进线粒体裂变，以应对已知扰乱线粒体形态的各种挑战。Mcl-1 诱导裂变可减少营养缺乏诱导的细胞死亡，并且保护作用与其 BH3 结构域无关。最后，Mcl-1 的心脏特异性过表达_OM，而不是 Mcl-1_矩阵，有助于平衡向裂变的转变，并导致运动能力降低，这表明预先存在的碎片化线粒体网络导致适应工作负荷和能量需求急剧增加的能力下降。总的来说，这些发现强调了 Mcl-1 在维持细胞线粒体健康方面的重要性。