SIRT3, a member of the sirtuin family of protein deacetylases, prevents cell aging by enhancing metabolic homeostasis through regulation of mitochondrial protein deacetylation. How it functions in tumor response to anticancer therapy is unknown. Liu and colleagues discovered that SIRT3 was transcriptionally regulated by NF-kB upon radiation, and its enzymatic activity was further enhanced via phosphorylation also by mitochondria-localized Cyclin B1/CDK1 complex. The phosphorylation of SIRT3 by CDK1 was required for mitochondrial functions as well as for cell survival tested by in vitro and in vivo radiation. Thus, targeting CDK1-SIRT3 phosphorylation-mediated mitochondrial metabolism provides an alternative approach to enhance tumor response to radiotherapy. For details, see the article by Liu and colleagues on page 2090.