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

Small-molecule inhibitors of enzyme function are critical tools for the study of cell biological processes and for treatment of human disease. Identifying inhibitors with suitable specificity and selectivity for single enzymes, however, remains a challenge. In this study we describe our serendipitous discovery that NMS-873, a compound that was previously identified as a highly selective allosteric inhibitor of the ATPase valosin-containing protein (VCP/p97), rapidly induces aerobic fermentation in cultured human and mouse cells. Our further investigation uncovered an unexpected off-target effect of NMS-873 on mitochondrial oxidative phosphorylation, specifically as a dual inhibitor of Complex I and ATP synthase. This work points to the need for caution regarding the interpretation of cell survival data associated with NMS-873 treatment and indicates that cellular toxicity associated with its use may be caused by both VCP/p97-dependent and VCP/p97-independent mechanisms. (c) 2021 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

Automated summary

The study found that NMS-873 rapidly induces aerobic fermentation in human and mouse cells and unexpectedly inhibits mitochondrial oxidative phosphorylation as a dual inhibitor of Complex I and ATP synthase. This suggests that caution is needed when interpreting cell survival data associated with NMS-873 treatment, as cellular toxicity may be caused by both VCP/p97-dependent and VCP/p97-independent mechanisms.