Tristetraprolin inhibits mitochondrial function through suppression of α-Synuclein expression in cancer cells

// Mai-Tram Vo 1 , Seong Hee Choi 1 , Ji-Heon Lee 2 , Chung Hwan Hong 1 , Jong Soo Kim 2 , Unn Hwa Lee 1 , Hyung-Min Chung 2 , Byung Ju Lee 1 , Jeong Woo Park 1 and Wha Ja Cho 1 1 Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Korea 2 Department of Stem Cell Biology, School of Medicine, Konkuk University, Gwangjin-Gu, Seoul, 143-701, Korea Correspondence to: Jeong Woo Park, email: jwpark@ulsan.ac.kr Wha Ja Cho, email: wjcho26@ulsan.ac.kr Keywords: tristetraprolin, mitochondrial dynamics, α-Synuclein Received: December 14, 2016 Accepted: March 19, 2017 Published: March 30, 2017 ABSTRACT Mitochondrial dynamics play critical roles in maintaining mitochondrial functions. Here, we report a novel mechanism for regulation of mitochondrial dynamics mediated by tristetraprolin (TTP), an AU-rich element (ARE)-binding protein. Overexpression of TTP resulted in elongated mitochondria, down-regulation of mitochondrial oxidative phosphorylation, reduced membrane potential, cytochrome c release, and increased apoptotic cell death in cancer cells. TTP overexpression inhibited the expression of α-Synuclein (α-Syn). TTP bound to the ARE within the mRNA 3'-untranslated regions (3′-UTRs) of α-Syn and enhanced the decay of α-Syn mRNA. Overexpression of α-Syn without the 3′-UTR restored TTP-induced defects in mitochondrial morphology, mitochondrial oxidative phosphorylation, membrane potential, and apoptotic cell death. Taken together, our data demonstrate that TTP acts as a regulator of mitochondrial dynamics through enhancing degradation of α-Syn mRNA in cancer cells. This finding will increase understanding of the molecular basis of mitochondrial dynamics.