Mitochondrial Localization of Telomeric Protein TIN2 Links Telomere Regulation to Metabolic Control

Liuh Yow Chen; Yi Zhang; Qinfen Zhang; Hongzhi Li; Zhenhua Luo; Hezhi Fang; Sok Ho Kim; Li Qin; Patricia Yotnda; Jianming Xu; Benjamin P. Tu; Yidong Bai; Zhou Songyang

doi:10.1016/j.molcel.2012.07.002

Mitochondrial Localization of Telomeric Protein TIN2 Links Telomere Regulation to Metabolic Control

Liuh Yow Chen, Yi Zhang, Qinfen Zhang, Hongzhi Li, Zhenhua Luo, Hezhi Fang, Sok Ho Kim, Li Qin, Patricia Yotnda, Jianming Xu, Benjamin P. Tu, Yidong Bai, Zhou Songyang

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77 Scopus citations

Abstract

Both mitochondria, which are metabolic powerhouses, and telomeres, which help maintain genomic stability, have been implicated in cancer and aging. However, the signaling events that connect these two cellular structures remain poorly understood. Here, we report that the canonical telomeric protein TIN2 is also a regulator of metabolism. TIN2 is recruited to telomeres and associates with multiple telomere regulators including TPP1. TPP1 interacts with TIN2 N terminus, which contains overlapping mitochondrial and telomeric targeting sequences, and controls TIN2 localization. We have found that TIN2 is posttranslationally processed in mitochondria and regulates mitochondrial oxidative phosphorylation. Reducing TIN2 expression by RNAi knockdown inhibited glycolysis and reactive oxygen species (ROS) production and enhanced ATP levels and oxygen consumption in cancer cells. These results suggest a link between telomeric proteins and metabolic control, providing an additional mechanism by which telomeric proteins regulate cancer and aging.

Original language	English (US)
Pages (from-to)	839-850
Number of pages	12
Journal	Molecular cell
Volume	47
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2012.07.002
State	Published - Sep 28 2012

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2012.07.002

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title = "Mitochondrial Localization of Telomeric Protein TIN2 Links Telomere Regulation to Metabolic Control",

abstract = "Both mitochondria, which are metabolic powerhouses, and telomeres, which help maintain genomic stability, have been implicated in cancer and aging. However, the signaling events that connect these two cellular structures remain poorly understood. Here, we report that the canonical telomeric protein TIN2 is also a regulator of metabolism. TIN2 is recruited to telomeres and associates with multiple telomere regulators including TPP1. TPP1 interacts with TIN2 N terminus, which contains overlapping mitochondrial and telomeric targeting sequences, and controls TIN2 localization. We have found that TIN2 is posttranslationally processed in mitochondria and regulates mitochondrial oxidative phosphorylation. Reducing TIN2 expression by RNAi knockdown inhibited glycolysis and reactive oxygen species (ROS) production and enhanced ATP levels and oxygen consumption in cancer cells. These results suggest a link between telomeric proteins and metabolic control, providing an additional mechanism by which telomeric proteins regulate cancer and aging.",

author = "Chen, {Liuh Yow} and Yi Zhang and Qinfen Zhang and Hongzhi Li and Zhenhua Luo and Hezhi Fang and Kim, {Sok Ho} and Li Qin and Patricia Yotnda and Jianming Xu and Tu, {Benjamin P.} and Yidong Bai and Zhou Songyang",

note = "Funding Information: We thank Drs. Fengtao Shi and Dong Yang for technical help, and Dr. Dan Liu for critical reading of this manuscript. This work is supported by National Basic Research Program (973 Program 2010CB945400 and 2012CB911201), National Natural Science Foundation of China (NSFC 91019020), NCI CA133249, NIGMS GM081627, GM095599, the Welch Foundation Q-1673, and the Leukemia and Lymphoma Society. This work is also supported by NIH grants DK058242 (J.X.) and 1R21NS072777 (Y.B.), the Dan L. Duncan Cancer Center (P30CA125123), and the Administrative and Genome-wide RNAi Screens Cores (IDDRC P30HD024064). ",

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T1 - Mitochondrial Localization of Telomeric Protein TIN2 Links Telomere Regulation to Metabolic Control

AU - Chen, Liuh Yow

AU - Zhang, Yi

AU - Zhang, Qinfen

AU - Li, Hongzhi

AU - Luo, Zhenhua

AU - Fang, Hezhi

AU - Kim, Sok Ho

AU - Qin, Li

AU - Yotnda, Patricia

AU - Xu, Jianming

AU - Tu, Benjamin P.

AU - Bai, Yidong

AU - Songyang, Zhou

N1 - Funding Information: We thank Drs. Fengtao Shi and Dong Yang for technical help, and Dr. Dan Liu for critical reading of this manuscript. This work is supported by National Basic Research Program (973 Program 2010CB945400 and 2012CB911201), National Natural Science Foundation of China (NSFC 91019020), NCI CA133249, NIGMS GM081627, GM095599, the Welch Foundation Q-1673, and the Leukemia and Lymphoma Society. This work is also supported by NIH grants DK058242 (J.X.) and 1R21NS072777 (Y.B.), the Dan L. Duncan Cancer Center (P30CA125123), and the Administrative and Genome-wide RNAi Screens Cores (IDDRC P30HD024064).

PY - 2012/9/28

Y1 - 2012/9/28

N2 - Both mitochondria, which are metabolic powerhouses, and telomeres, which help maintain genomic stability, have been implicated in cancer and aging. However, the signaling events that connect these two cellular structures remain poorly understood. Here, we report that the canonical telomeric protein TIN2 is also a regulator of metabolism. TIN2 is recruited to telomeres and associates with multiple telomere regulators including TPP1. TPP1 interacts with TIN2 N terminus, which contains overlapping mitochondrial and telomeric targeting sequences, and controls TIN2 localization. We have found that TIN2 is posttranslationally processed in mitochondria and regulates mitochondrial oxidative phosphorylation. Reducing TIN2 expression by RNAi knockdown inhibited glycolysis and reactive oxygen species (ROS) production and enhanced ATP levels and oxygen consumption in cancer cells. These results suggest a link between telomeric proteins and metabolic control, providing an additional mechanism by which telomeric proteins regulate cancer and aging.

AB - Both mitochondria, which are metabolic powerhouses, and telomeres, which help maintain genomic stability, have been implicated in cancer and aging. However, the signaling events that connect these two cellular structures remain poorly understood. Here, we report that the canonical telomeric protein TIN2 is also a regulator of metabolism. TIN2 is recruited to telomeres and associates with multiple telomere regulators including TPP1. TPP1 interacts with TIN2 N terminus, which contains overlapping mitochondrial and telomeric targeting sequences, and controls TIN2 localization. We have found that TIN2 is posttranslationally processed in mitochondria and regulates mitochondrial oxidative phosphorylation. Reducing TIN2 expression by RNAi knockdown inhibited glycolysis and reactive oxygen species (ROS) production and enhanced ATP levels and oxygen consumption in cancer cells. These results suggest a link between telomeric proteins and metabolic control, providing an additional mechanism by which telomeric proteins regulate cancer and aging.

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Mitochondrial Localization of Telomeric Protein TIN2 Links Telomere Regulation to Metabolic Control

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