As stated by the authors, the molecular details for how MFF regulates VDAC1-directed mitochondrial outer membrane potential permeability remain to be fully elucidated. A few important questions remain unanswered and are critical for the pragmatic translation of these findings. Given the importance of VDAC proteins toward mitochondrial function and tumor cell death from this and other reports, it is intriguing to consider the targeting of VDAC via its well-characterized interface with MFF1 as a potential strategy for anticancer therapy ( 5). To create a cell-permeable peptide, the authors added an amino-terminus HIV-Tat cell penetrating sequence to their optimized MFF peptide and showed cytochrome c release, loss of mitochondrial integrity, and cell killing in multiple cancer cell lines treated with this peptide but not in normal cells or cells treated with scrambled peptides. To confirm molecular modeling predictions, one MFF peptide was selected as a selective competitive inhibitor of the MFF–VDAC1 complex in multiple cancer cell lines using coimmunoprecipitation and membrane depolarization experiments. Using these results, the authors proposed the key residues in MFF1/2 that coordinate the binding interface with VDAC1. VDAC1 binding studies using isothermal titration calorimetry were used to quantify the dissociation constants ( K d) of the peptides with VDAC1 and molecular modeling was used to place the peptide with optimal K d in the anterior hole of the VDAC1 ring. Orthogonal analytic techniques were used to demonstrate the kinetics and molecular dynamics of interaction between the proposed MFF peptide and recombinant human VDAC1. These peptides depolarized mitochondria selectively in isolated prostate PC-3 tumor mitochondria but not BPH-1 cell line–derived mitochondria. Extensive characterization of the structural attributes and sequences required for binding with VDAC led to the identification of peptides that correspond to specific regions of the MFF sequence (Asp271-Leu 246). This article is the first to report that MFF1 is elevated in NSCLC compared with healthy bronchus tissue, and the authors performed an in-depth structural characterization study of the MFF1/2 interaction with VDAC using multiple cancer models. In this study, overexpression of MFF was confirmed using non–small cell lung cancer (NSCLC) patient tissue and healthy bronchus tissue samples. Building on previous work that identified mitochondrial fission factor (MFF) as a transcriptional target of oncogenic Myc overexpressed in primary and metastatic prostate cancer ( 4), Seo and colleagues provide compelling evidence for complex formation between MFF and voltage-dependent anion channel (VDAC) at the mitochondrial outer membrane in multiple tumor versus healthy models of prostate, breast, melanoma, and glioblastoma ( 3). If drug developers are to successfully leverage mitochondrial cell death toward anticancer activity, it would be critical to identify and target a discerning mitochondrial mechanism that is selectively and prominently featured in a cancer cell's ability to survive and evade surveillance mechanisms ( 1–3). The ultimate fate of these cells is determined by a highly complex and evolved network of checkpoints and molecular signals within the mitochondria, some of which result in cell death but are subverted in cancer. On a cellular level, these disruptions can trigger a shift in metabolic programming toward glycolysis (the Warburg effect), altered mitochondrial membrane potential, increased superoxide production, and promotion of tumor metastasis or cell migration ( 1). However, mitochondrial dynamics can be disrupted by external stimuli such as drugs, environment toxicants, radiation, or infections. The biogenesis of and functions within mitochondria are primarily controlled by nuclear DNA. Mitochondrial dysfunction is therefore linked to a range of physiologic problems like diabetes, neuropathy, cardiovascular disease, and cancer. The unique role of mitochondria in living cells related to metabolism and generation of energy is at the core of its essential nature.