Journal Article

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

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

2019

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine Triphosphate - biosynthesis / Alzheimer's disease / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Animal models / Animals / ATP-Dependent Proteases - genetics / ATP-Dependent Proteases - metabolism / Biology and Life Sciences / Biophysics / Brain - metabolism / Brain - pathology / Brain research / Cancer / Causes of / Cristae / Dementia / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drosophila melanogaster / Electron microscopy / Electron transport chain / Electron Transport Complex I - genetics / Electron Transport Complex I - metabolism / Frontotemporal dementia / Frontotemporal Lobar Degeneration - genetics / Frontotemporal Lobar Degeneration - metabolism / Frontotemporal Lobar Degeneration - pathology / Funding / Gene Expression Regulation / Genes / Genetic aspects / Health aspects / HEK293 Cells / Homeostasis / Humans / Insects / Laboratories / Medical research / Medicine / Medicine and Health Sciences / Membrane potential / Membrane Potential, Mitochondrial - genetics / Microscopy / Mitochondria / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Mutation / NADH-ubiquinone oxidoreductase / Nervous system diseases / Neurodegeneration / Neurodegenerative diseases / Neurology / Pathology / Patients / Physiological aspects / Proteases / Protein folding / Proteins / Reactive oxygen species / Reactive Oxygen Species - metabolism / Research and Analysis Methods / Signal Transduction / TDP-43 Proteinopathies - genetics / TDP-43 Proteinopathies - metabolism / TDP-43 Proteinopathies - pathology / Tetracyclines / Unfolded Protein Response