LAUSR

Apoptosis-inducing factor has two roles: acting as an apoptosis effector and maintaining mitochondrial metabolism. A recent study uncouples these roles and finds that only the mitochondrial functions are required for tumorigenesis in mice. Hallmarks of malignancy include evasion of apoptotic signals and altered cellular metabolism to support growth and proliferation. However, there is significant overlap between metabolic and apoptotic functions in the mitochondria, and untangling the precise contribution of each to tumorigenesis poses a significant challenge because several proteins contribute to both pathways. Apoptosis-inducing factor (AIF) was first described as a caspaseindependent apoptosis effector. During induction of apoptosis, AIF translocates from the mitochondria to the nucleus, triggering chromatin condensation and DNA fragmentation. Early studies also found that reduction of AIF protein renders cells susceptible to peroxide-induced apoptosis, suggesting a functional role in oxidative phosphorylation (OXPHOS) and redox control. Multiple models have since elucidated the roles of AIF in mitochondrial respiration. Most consistently, genetic deletion of AIF (or its binding partner CHCHD4) results in decreased protein levels of respiratory complex I, and consequently impaired OXPHOS. Which biological functions of AIF are important for tumor growth and development? Rao et al. explore the role of AIF in lung cancer using genetic mouse models in which KRAS drives tumorigenesis in the presence or absence of AIF. They began by noting increased AIF protein levels in non-small cell lung cancer (NSCLC) compared to the adjacent non-involved lung tissues. However, in contrast to what the authors expected to find after removing AIF (increased tumor formation), they surprisingly observed that loss of AIF actually impaired lung tumor initiation, resulting in decreased tumor burden and prolonged survival of the mice. Thus, AIF was acting like an oncoprotein rather than a tumor suppressor. AIF loss was characterized by decreased