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

Peng Wang, Jianwen Deng, Jie Dong, Jianghong Liu, Eileen H. Bigio, Marsel Mesulam, Tao Wang, Lei Sun, Li Wang, Alan Yueh Luen Lee, Warren A. McGee, Xiaoping Chen, Kazuo Fushimi, Li Zhu, Jane Y. Wu*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Scopus citations


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. Downregulating 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.

Original languageEnglish (US)
Article numbere1007947
JournalPLoS genetics
Issue number5
StatePublished - May 2019


ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Wang, P., Deng, J., Dong, J., Liu, J., Bigio, E. H., Mesulam, M., Wang, T., Sun, L., Wang, L., Lee, A. Y. L., McGee, W. A., Chen, X., Fushimi, K., Zhu, L., & Wu, J. Y. (2019). TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLoS genetics, 15(5), [e1007947].