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二甲双胍通过改变癌细胞内钙离子流来破坏线粒体的完整性，从而达到干扰肿瘤细胞能量代谢的目的。

The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells.

机构信息

Inserm U1065, C3M, Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France.

Université Nice Côte d'Azur, Inserm, Nice, France.

出版信息

Sci Rep. 2017 Jul 11;7(1):5040. doi: 10.1038/s41598-017-05052-2.

DOI:10.1038/s41598-017-05052-2
PMID:28698627
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5506014/
Abstract

Mitochondrial integrity is critical for the regulation of cellular energy and apoptosis. Metformin is an energy disruptor targeting complex I of the respiratory chain. We demonstrate that metformin induces endoplasmic reticulum (ER) stress, calcium release from the ER and subsequent uptake of calcium into the mitochondria, thus leading to mitochondrial swelling. Metformin triggers the disorganization of the cristae and inner mitochondrial membrane in several cancer cells and tumors. Mechanistically, these alterations were found to be due to calcium entry into the mitochondria, because the swelling induced by metformin was reversed by the inhibition of mitochondrial calcium uniporter (MCU). We also demonstrated that metformin inhibits the opening of mPTP and induces mitochondrial biogenesis. Altogether, the inhibition of mPTP and the increase in mitochondrial biogenesis may account for the poor pro-apoptotic effect of metformin in cancer cells.

摘要

线粒体完整性对于细胞能量和细胞凋亡的调节至关重要。二甲双胍是一种靶向呼吸链复合物 I 的能量破坏剂。我们证明二甲双胍诱导内质网 (ER) 应激，钙从 ER 释放，随后钙进入线粒体，从而导致线粒体肿胀。二甲双胍引发几种癌细胞和肿瘤中线粒体嵴和内膜的解聚。从机制上讲，这些变化是由于钙进入线粒体，因为通过抑制线粒体钙单向转运蛋白 (MCU) 可逆转二甲双胍诱导的肿胀。我们还证明二甲双胍抑制 mPTP 的开放并诱导线粒体生物发生。总之，mPTP 的抑制和线粒体生物发生的增加可能是二甲双胍在癌细胞中促凋亡作用不佳的原因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/cd772d6b73ce/41598_2017_5052_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/34aa4026b055/41598_2017_5052_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/02f8f58d9511/41598_2017_5052_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/f79b31054568/41598_2017_5052_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/453e9b63c88d/41598_2017_5052_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/cd772d6b73ce/41598_2017_5052_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/34aa4026b055/41598_2017_5052_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/02f8f58d9511/41598_2017_5052_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/f79b31054568/41598_2017_5052_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/453e9b63c88d/41598_2017_5052_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50c5/5506014/cd772d6b73ce/41598_2017_5052_Fig5_HTML.jpg

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