Oncotarget

Research Papers:

Establishment of mitochondrial pyruvate carrier 1 (MPC1) gene knockout mice with preliminary gene function analyses

Xiaoli Li _, Yaqing Li, Gaoyang Han, Xiaoran Li, Yasai Ji, Zhirui Fan, Yali Zhong, Jing Cao, Jing Zhao, Goscinski Mariusz, Mingzhi Zhang, Jianguo Wen, Jahn M. Nesland and Zhenhe Suo

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Oncotarget. 2016; 7:79981-79994. https://doi.org/10.18632/oncotarget.13210

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Abstract

Xiaoli Li1,2, Yaqing Li1,2, Gaoyang Han3, Xiaoran Li2, Yasai Ji1, Zhirui Fan1, Yali Zhong1, Jing Cao1,4, Jing Zhao1, Goscinski Mariusz5, Mingzhi Zhang1, Jianguo Wen6, Jahn M. Nesland2, Zhenhe Suo1,2

1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

2Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Montebello, Oslo, Norway

3Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui City, Henan Province, China

4Department of Pathology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

5Department of Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway

6The Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

Correspondence to:

Zhenhe Suo, email: zhenhes@medisin.uio.no, zhenhesuo@aliyun.com

Keywords: MPC1, CRISPR/Cas9, diabetes, gene knockout, reproductive capability

Received: June 13, 2016     Accepted: October 19, 2016     Published: November 08, 2016

ABSTRACT

Pyruvate plays a critical role in the mitochondrial tricarboxylic acid (TCA) cycle, and it is the center product for the synthesis of amino acids, carbohydrates and fatty acids. Pyruvate transported across the inner mitochondrial membrane appears to be essential in anabolic and catabolic intermediary metabolism. The mitochondrial pyruvate carrier (MPC) mounted in the inner membrane of mitochondria serves as the channel to facilitate pyruvate permeating. In mammals, the MPC is formed by two paralogous subunits, MPC1 and MPC2. It is known that complete ablation of MPC2 in mice causes death on the 11th or 12th day of the embryonic period. However, MPC1 deletion and the knowledge of gene function in vivo are lacking. Using the new technology of gene manipulation known as Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9 (CRISPR/Cas9) systems, we gained stable MPC1 gene heterozygous mutation mice models, and the heterozygous mutations could be stably maintained in their offsprings. Only one line with homozygous 27 bases deletion in the first exon was established, but no offsprings could be obtained after four months of mating experiments, indicating infertility of the mice with such homozygous deletion. The other line of MPC1 knockout (KO) mice was only heterozygous, which mutated in the first exon with a terminator shortly afterwards. These two lines of MPC1 KO mice showed lower fertility and significantly higher bodyweight in the females. We concluded that heterozygous MPC1 KO weakens fertility and influences the metabolism of glucose and fatty acid and bodyweight in mice.


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