Mitochondria are highly motile organelles that constantly undergo fission and fusion. Impairment of mitochondrial dynamics is associated with mitochondrial dysfunction and frequently linked to the pathogenesis of neurodegenerative diseases and cancer. We have previously shown that loss-of-function of suppressor of cytokine signaling (SOCS) 6 is a frequent event in human gastric cancer and ectopic expression of SOCS6 sensitized cells to UV-induced apoptosis. In this study, we have identified SOCS6 as a novel mitochondrial protein that regulates mitochondrial dynamics. By confocal microscopy, we showed that ectopically expressed SOCS6 is predominantly localized in mitochondria, and that the carboxyl-terminal SOCS box is important for its mitochondrial localization. We further showed that localization of SOCS6 in mitochondria is accompanied with increased mitochondrial fragmentation with attenuated membrane potential, both of which can be reversed by coexpression of mitochondrial fusion proteins Mfn1 or Mfn2. Our data further suggested that SOCS6 interferes with mitochondrial dynamics by interrupting the fusion process. Firstly, SOCS6 expression severely impaired the dynamics and mobility of mitochondria in live cells as demonstrated by fluorescence recovery after photobleaching (FRAP) experiments. Secondly, SOCS6 expression significantly hampered intermitochondrial transfer and fusion in the somatic hybrid produced by PEG-induced fusion. Furthermore, elimination of the expression of endogenous SOCS6 by RNA interference technique led to elongated mitochondria, and conferred cells increased resistance to UV-induced apoptosis. Taken together, our data suggest that SOCS6 is a mitochondrial targeting protein involved in the regulation of mitochondrial dynamics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1208.