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现在位置:首页 > 科研进展 > 最新重要论文(影响因子PNAS及以上)
TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response, PLOS Genetics, 17 May 2019
2019-05-01 | 【     】【打印】【关闭

PLOS Genetics, 17 May, 2019, DOI: http://dx.doi.org/10.1371/journal.pgen.1007947

TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response

Wang P#, Deng J#, Dong J, Liu J, Bigio EH, Mesulam M, Wang T, Sun L, Wang L, Lee AY, McGee WA, Chen X, Fushimi K, Zhu L*, and Wu JY*

Abstract

Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.

文章链接:https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007947

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