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- Title
TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response.
- Authors
Wang, Peng; Deng, Jianwen; Dong, Jie; Liu, Jianghong; Bigio, Eileen H.; Mesulam, Marsel; Wang, Tao; Sun, Lei; Wang, Li; Lee, Alan Yueh-Luen; McGee, Warren A.; Chen, Xiaoping; Fushimi, Kazuo; Zhu, Li; Wu, Jane Y.
- 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.
- Subjects
GENETIC mutation; NEURODEGENERATION; AMYOTROPHIC lateral sclerosis; ANIMAL models in research; GENE expression; ADENOSINE triphosphate; UNFOLDED protein response; MITOCHONDRIA
- Publication
PLoS Genetics, 2019, Vol 15, Issue 5, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1007947