Journal Article

Suppressor of cytokine signaling 6 (SOCS6) promotes mitochondrial fission via regulating DRP1 translocation

Wang, M-J, Lin, H-Y, Wang, F-F, Lai, R-H, Lin, R-C, Lin, C-C, Lin, S-T, Lee, H-C, Chen, J-Y

2013

Overview

Mitochondria are highly motile organelles that constantly undergo fission and fusion. Impairment of mitochondrial dynamics is associated with mitochondrial dysfunction and is frequently linked to the pathogenesis of neurodegenerative diseases and cancer. We have previously shown that biallelic inactivation of the suppressor of cytokine signaling 6 ( SOCS6 ) gene is a frequent event in human gastric cancer. In this study, we recapitulated the event of SOCS6 loss using a Lentivirus-based knockdown approach, and demonstrated the linkage between SOCS6 depletion and the suppression of programmed cell death. SOCS6 promotes intrinsic apoptosis, with increased Bax conformational change, mitochondrial targeting, and oligomerization. Most importantly, SOCS6 is targeted to mitochondria and induces mitochondrial fragmentation mediated through an increase in DRP1 fission activity. Here, we show that SOCS6 forms complex with DRP1 and the mitochondrial phosphatase PGAM5, attenuates DRP1 phosphorylation, and promotes DRP1 mitochondrial translocation. Based on mutation analyses, SOCS6-mediated apoptosis is tightly coupled to its ability to induce mitochondrial fission. This study demonstrates an important role for SOCS6 in modulating mitochondrial dynamics and apoptosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/80/642/333 / 631/80/82/23 / 631/80/86 / Apoptosis / Apoptosis - genetics / Apoptosis - physiology / Bax protein / Biochemistry / Biomedical and Life Sciences / Carrier Proteins - metabolism / Cell Biology / Cell Cycle Analysis / Cell death / Cytochrome / Cytokines / Gastric cancer / Gene Knockdown Techniques / Gene Silencing / GTP Phosphohydrolases - genetics / GTP Phosphohydrolases - metabolism / HEK293 Cells / Humans / Kinases / Life Sciences / Microtubule-Associated Proteins - genetics / Microtubule-Associated Proteins - metabolism / Mitochondria / Mitochondria - metabolism / Mitochondria - physiology / Mitochondrial Dynamics - genetics / Mitochondrial Dynamics - physiology / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Molecular biology / Mutation / Neurodegenerative diseases / Oligomerization / Organelles / Original Paper / Phosphatase / Phosphoprotein Phosphatases / Phosphorylation / Protein Transport / Proteins / Signal Transduction / Stem Cells / Suppressor of Cytokine Signaling Proteins - deficiency / Suppressor of Cytokine Signaling Proteins - genetics / Suppressor of Cytokine Signaling Proteins - metabolism / Translocation / Tumor necrosis factor-TNF