MCL-1, an anti-apoptotic protein, promotes long chain fatty acid oxidation (FAO) by interacting with ACSL1, a key enzyme in mitochondrial FA import. This interaction occurs through a non-conventional BH3-domain of MCL-1 binding to a BH3-like domain of ACSL1. Disrupting this interaction, via genetic loss of Mcl1, mutagenesis, or BH3-mimetic inhibitors, represses long chain FAO in cells and tissues, potentially causing cardiac toxicity in clinical trials. MCL-1 is localized to the outer mitochondrial membrane (OMM) and supports mitochondrial dynamics and oxidative phosphorylation. Its loss in liver and heart tissues leads to reduced long chain FAO, as evidenced by lipid accumulation and impaired FA oxidation. MCL-1 interacts with ACSL1 at the OMM, and this interaction is regulated by the hydrophobic BH3-binding groove of MCL-1. Structural studies show that ACSL1's BH3-like domain binds to MCL-1's BH3-binding groove. MCL-1 inhibitors, such as AZD5991, disrupt this interaction, repressing long chain FAO. In cardiomyocytes, MCL-1 loss or inhibition represses FAO, leading to reduced ATP production and potential cardiac damage. These findings highlight the critical role of MCL-1 in mitochondrial metabolism and suggest that MCL-1 inhibitors may cause cardiac toxicity due to impaired FAO. The study also indicates that MCL-1 and ACSL1 interactions are essential for normal cellular function and that their disruption can lead to metabolic and apoptotic dysregulation.MCL-1, an anti-apoptotic protein, promotes long chain fatty acid oxidation (FAO) by interacting with ACSL1, a key enzyme in mitochondrial FA import. This interaction occurs through a non-conventional BH3-domain of MCL-1 binding to a BH3-like domain of ACSL1. Disrupting this interaction, via genetic loss of Mcl1, mutagenesis, or BH3-mimetic inhibitors, represses long chain FAO in cells and tissues, potentially causing cardiac toxicity in clinical trials. MCL-1 is localized to the outer mitochondrial membrane (OMM) and supports mitochondrial dynamics and oxidative phosphorylation. Its loss in liver and heart tissues leads to reduced long chain FAO, as evidenced by lipid accumulation and impaired FA oxidation. MCL-1 interacts with ACSL1 at the OMM, and this interaction is regulated by the hydrophobic BH3-binding groove of MCL-1. Structural studies show that ACSL1's BH3-like domain binds to MCL-1's BH3-binding groove. MCL-1 inhibitors, such as AZD5991, disrupt this interaction, repressing long chain FAO. In cardiomyocytes, MCL-1 loss or inhibition represses FAO, leading to reduced ATP production and potential cardiac damage. These findings highlight the critical role of MCL-1 in mitochondrial metabolism and suggest that MCL-1 inhibitors may cause cardiac toxicity due to impaired FAO. The study also indicates that MCL-1 and ACSL1 interactions are essential for normal cellular function and that their disruption can lead to metabolic and apoptotic dysregulation.