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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

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. 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
Volume15
Issue number5
DOIs
StatePublished - May 1 2019

Fingerprint

TDP-43 Proteinopathies
unfolded protein response
Unfolded Protein Response
Mitochondrial Proteins
animal models
damage
protein
Animal Models
animal
neurodegenerative diseases
membrane potential
Frontotemporal Lobar Degeneration
reactive oxygen species
electron microscopy
proteinases
Mitochondrial Membrane Potential
defect
mutation
brain
Amyotrophic Lateral Sclerosis

ASJC Scopus subject areas

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

Cite this

Wang, Peng ; Deng, Jianwen ; Dong, Jie ; Liu, Jianghong ; Bigio, Eileen H ; Mesulam, Marek-Marsel ; Wang, Tao ; Sun, Lei ; Wang, Li ; Lee, Alan Yueh Luen ; McGee, Warren A. ; Chen, Xiaoping ; Fushimi, Kazuo ; Zhu, Li ; Wu, Jane. / TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. In: PLoS genetics. 2019 ; Vol. 15, No. 5.
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title = "TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response",
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. 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.",
author = "Peng Wang and Jianwen Deng and Jie Dong and Jianghong Liu and Bigio, {Eileen H} and Marek-Marsel Mesulam and Tao Wang and Lei Sun and Li Wang and Lee, {Alan Yueh Luen} and McGee, {Warren A.} and Xiaoping Chen and Kazuo Fushimi and Li Zhu and Jane Wu",
year = "2019",
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doi = "10.1371/journal.pgen.1007947",
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Wang, P, Deng, J, Dong, J, Liu, J, Bigio, EH, Mesulam, M-M, Wang, T, Sun, L, Wang, L, Lee, AYL, McGee, WA, Chen, X, Fushimi, K, Zhu, L & Wu, J 2019, 'TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response', PLoS genetics, vol. 15, no. 5, e1007947. https://doi.org/10.1371/journal.pgen.1007947

TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. / Wang, Peng; Deng, Jianwen; Dong, Jie; Liu, Jianghong; Bigio, Eileen H; Mesulam, Marek-Marsel; Wang, Tao; Sun, Lei; Wang, Li; Lee, Alan Yueh Luen; McGee, Warren A.; Chen, Xiaoping; Fushimi, Kazuo; Zhu, Li; Wu, Jane.

In: PLoS genetics, Vol. 15, No. 5, e1007947, 01.05.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response

AU - Wang, Peng

AU - Deng, Jianwen

AU - Dong, Jie

AU - Liu, Jianghong

AU - Bigio, Eileen H

AU - Mesulam, Marek-Marsel

AU - Wang, Tao

AU - Sun, Lei

AU - Wang, Li

AU - Lee, Alan Yueh Luen

AU - McGee, Warren A.

AU - Chen, Xiaoping

AU - Fushimi, Kazuo

AU - Zhu, Li

AU - Wu, Jane

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

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