The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons

• Published in: Human molecular genetics Vol. 22; no. 23; pp. 4706 - 4719
• Main Authors: Wang, Wenzhang, Li, Li, Lin, Wen-Lang, Dickson, Dennis W., Petrucelli, Leonard, Zhang, Teng, Wang, Xinglong
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.12.2013
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Cells, Cultured; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Female; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Male; Membrane Proteins - physiology; Mitochondria - physiology; Mitochondria - ultrastructure; Mitochondrial Dynamics; Mitochondrial Proteins - physiology; Motor Neurons - pathology; Motor Neurons - physiology; Mutation; Neurites - metabolism; Neurites - ultrastructure; Pregnancy; Rats; Rats, Sprague-Dawley; Rats, Transgenic
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddt319

Mutations in TDP-43 lead to familial ALS. Expanding evidence suggests that impaired mitochondrial dynamics likely contribute to the selective degeneration of motor neurons in SOD1-associated ALS. In this study, we investigated whether and how TDP-43 mutations might impact mitochondrial dynamics and function. We demonstrated that overexpression of wild-type TDP-43 resulted in reduced mitochondrial length and density in neurites of primary motor neurons, features further exacerbated by ALS-associated TDP-43 mutants Q331K and M337V. In contrast, suppression of TDP-43 resulted in significantly increased mitochondrial length and density in neurites, suggesting a specific role of TDP-43 in regulating mitochondrial dynamics. Surprisingly, both TDP-43 overexpression and suppression impaired mitochondrial movement. We further showed that abnormal localization of TDP-43 in cytoplasm induced substantial and widespread abnormal mitochondrial dynamics. TDP-43 co-localized with mitochondria in motor neurons and their colocalization was enhanced by ALS associated mutant. Importantly, co-expression of mitochondrial fusion protein mitofusin 2 (Mfn2) could abolish TDP-43 induced mitochondrial dynamics abnormalities and mitochondrial dysfunction. Taken together, these data suggest that mutant TDP-43 impairs mitochondrial dynamics through enhanced localization on mitochondria, which causes mitochondrial dysfunction. Therefore, abnormal mitochondrial dynamics is likely a common feature of ALS which could be potential new therapeutic targets to treat ALS.