小柯机器人

近日，芬兰赫尔辛基大学Anu Suomalainen课题组研究发现成纤维细胞生长因子21（FGF21）驱动线粒体DNA(mtDNA)缺失时，线粒体肌病局部和全身应激反应的动力学。这一研究成果2019年9月12日在线发表于《细胞—代谢》。

研究人员发现，在线粒体肌病中，线粒体综合应激反应（ISRmt）会在某一暂时阶段进展，并从早期发展到一个长期的过程，并受FGF21的自分泌和内分泌作用调节，FGF21是一种具有多效作用的代谢激素。最初的疾病体征诱导转录型的ISRmt（ATF5，线粒体单碳循环，FGF21和GDF15）。局部进展到第二代谢ISRmt阶段（ATF3，ATF4，葡萄糖摄取，丝氨酸生物合成和转硫化）是FGF21依赖性的。线粒体未折叠蛋白应答标志着损坏组织的第3个ISRmt阶段。FGF21会系统性的驱动体重减轻和葡萄糖偏好，并且改变特定海马脑区域的代谢和呼吸链缺陷。证据表明，FGF21是患有类线粒体疾病的小鼠和人mtDNA应激的局部和系统信使。

据介绍，线粒体功能障碍引发应激反应，保护细胞稳态免受代谢损伤。ISRmt是线粒体（mt）DNA表达应激（mtDNA维持，翻译缺陷）的主要反应，但对于动力学或组分相互依赖性仍然缺乏认知。

附：英文原文

Title: Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

Author: Saara Forsstrm, Christopher B. Jackson, Christopher J. Carroll, Mervi Kuronen, Eija Pirinen, Swagat Pradhan, Anastasiia Marmyleva, Mari Auranen, Iida-Marja Kleine, Nahid A. Khan, Anne Roivainen, Pivi Marjamki, Heidi Liljenbck, Liya Wang, Brendan J. Battersby, Uwe Richter, Vidya Velagapudi, Joni Nikkanen, Liliya Euro, Anu Suomalainen

Issue&Volume: 12 September 2019

Summary: 

Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISR mt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISR mt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISR mt (ATF5, mitochondrial one-carbon cycle, FGF21, and GDF15). The local progression to 2 nd metabolic ISR mt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondrial unfolded protein response marks the 3 rd ISR mt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.

DOI: 10.1016/j.cmet.2019.08.019

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30448-6

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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