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ABSTRACT: Mitochondria amplify caspase-dependent apoptosis by releasing proapoptotic proteins, especially cytochrome c. This process is accompanied by mitochondrial cristae remodeling. Our studies demonstrated that mitofilin, a mitochondrial inner membrane protein, acted as a cristae controller to regulate cytochrome c release during apoptosis. Knockdown of mitofilin in HeLa cells with RNAi led to fragmentation of the mitochondrial network and disorganization of the cristae. Mitofilin-deficient cells showed cytochrome c redistribution between mitochondrial cristae and the intermembrane space (IMS) upon intrinsic apoptotic stimuli. In vitro cytochrome c release experiments further confirmed that, compared with the control group, tBid treatment led to an increase in cytochrome c release from mitofilin-deficient mitochondria. Furthermore, the cells with mitofilin knockdown were more prone to apoptosis by accelerating cytochrome c release upon the intrinsic apoptotic stimuli than controls. Moreover, mitofilin deficiency did not interfere with the activation of proapoptotic member Bax upon intrinsic apoptotic stimuli. Thus, mitofilin distinctly functions in cristae remodeling and controls cytochrome c release during apoptosis.
Biochemical and Biophysical Research Communications 10/2012; · 2.48 Impact Factor
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Ran Zhang,
Hou-Zao Chen,
Jin-Jing Liu,
Yu-Yan Jia,
Zhu-Qin Zhang,
Rui-Feng Yang, Yuan Zhang,
Jing Xu,
Yu-Sheng Wei,
De-Pei Liu,
Chih-Chuan Liang
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ABSTRACT: SIRT1 (Sirtuin type 1), a mammalian orthologue of yeast SIR2 (silent information regulator 2), has been shown to mediate a variety of calorie restriction (CR)-induced physiological events, such as cell fate regulation via deacetylation of the substrate proteins. However, whether SIRT1 deacetylates activator protein-1 (AP-1) to influence its transcriptional activity and target gene expression is still unknown. Here we demonstrate that SIRT1 directly interacts with the basic leucine zipper domains of c-Fos and c-Jun, the major components of AP-1, by which SIRT1 suppressed the transcriptional activity of AP-1. This process requires the deacetylase activity of SIRT1. Notably, SIRT1 reduced the expression of COX-2, a typical AP-1 target gene, and decreased prostaglandin E(2) (PGE(2)) production of peritoneal macrophages (pMPhis). pMPhis with SIRT1 overexpression displayed improved phagocytosis and tumoricidal functions, which are associated with depressed PGE(2). Furthermore, SIRT1 protein level was up-regulated in CR mouse pMPhis, whereas elevated SIRT1 decreased COX-2 expression and improved PGE(2)-related macrophage functions that were reversed following inhibition of SIRT1 deacetylase activity. Thus, our results indicate that SIRT1 may be a mediator of CR-induced macrophage regulation, and its deacetylase activity contributes to the inhibition of AP-1 transcriptional activity and COX-2 expression leading to amelioration of macrophage function.
Journal of Biological Chemistry 03/2010; 285(10):7097-110. · 4.77 Impact Factor
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Ran Zhang,
Hou-Zao Chen,
Jin-Jing Liu,
Yu-Yan Jia,
Zhu-Qin Zhang,
Rui-Feng Yang, Yuan Zhang,
Jing Xu,
Yu-Sheng Wei,
De-Pei Liu,
Chih-Chuan Liang
[show abstract]
[hide abstract]
ABSTRACT: SIRT1 (Sirtuin type 1), a mammalian orthologue of yeast SIR2 (silent information regulator 2), has been shown to mediate a
variety of calorie restriction (CR)-induced physiological events, such as cell fate regulation via deacetylation of the substrate
proteins. However, whether SIRT1 deacetylates activator protein-1 (AP-1) to influence its transcriptional activity and target
gene expression is still unknown. Here we demonstrate that SIRT1 directly interacts with the basic leucine zipper domains
of c-Fos and c-Jun, the major components of AP-1, by which SIRT1 suppressed the transcriptional activity of AP-1. This process
requires the deacetylase activity of SIRT1. Notably, SIRT1 reduced the expression of COX-2, a typical AP-1 target gene, and
decreased prostaglandin E2 (PGE2) production of peritoneal macrophages (pMΦs). pMΦs with SIRT1 overexpression displayed improved phagocytosis and tumoricidal
functions, which are associated with depressed PGE2. Furthermore, SIRT1 protein level was up-regulated in CR mouse pMΦs, whereas elevated SIRT1 decreased COX-2 expression and
improved PGE2-related macrophage functions that were reversed following inhibition of SIRT1 deacetylase activity. Thus, our results indicate
that SIRT1 may be a mediator of CR-induced macrophage regulation, and its deacetylase activity contributes to the inhibition
of AP-1 transcriptional activity and COX-2 expression leading to amelioration of macrophage function.
Journal of Biological Chemistry 03/2010; 285(10):7097-7110. · 4.77 Impact Factor
