NMS-873 functions as a dual inhibitor of mitochondrial oxidative phosphorylation

Small-molecule inhibitors of enzyme function are essential tools for studying cellular processes and treating human diseases. However, identifying inhibitors with the appropriate specificity and selectivity for individual enzymes remains a challenge. In this study, we report a serendipitous finding that NMS-873, a compound previously identified as a highly selective allosteric inhibitor of the ATPase valosin-containing protein (VCP/p97), unexpectedly induces aerobic fermentation in cultured human and mouse cells. Further investigation revealed an unforeseen off-target effect of NMS-873 on mitochondrial oxidative phosphorylation, specifically inhibiting both Complex I and ATP synthase. This work highlights the need for caution when interpreting cell survival data related to NMS-873 treatment and suggests that the cellular toxicity observed may result from both VCP/p97-dependent and VCP/p97-independent mechanisms.