TDP-43 proteinopathy and mitochondrial abnormalities in neurodegeneration

Ju Gao, L. Wang, Tingxiang Yan, George Perry, Xinglong Wang

Research output: Contribution to journalReview articlepeer-review

57 Scopus citations


Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Importantly, TDP-43 proteinopathy, characterized by aberrant phosphorylation, ubiquitination, cleavage or nuclear depletion of TDP-43 in neurons and glial cells, is a common prominent pathological feature of various major neurodegenerative diseases including ALS, FTD, and Alzheimer's disease (AD). Although the pathomechanisms underlying TDP-43 proteinopathy remain elusive, pathologically relevant TDP-43 has been repeatedly shown to be present in either the inside or outside of mitochondria, and functionally involved in the regulation of mitochondrial morphology, trafficking, and function, suggesting mitochondria as likely targets of TDP-43 proteinopathy. In this review, we first describe the current knowledge of the association of TDP-43 with mitochondria. We then review in detail multiple mitochondrial pathways perturbed by pathological TDP-43, including mitochondrial fission and fusion dynamics, mitochondrial trafficking, bioenergetics, and mitochondrial quality control. Lastly, we briefly discuss how the study of TDP-43 proteinopathy and mitochondrial abnormalities may provide new avenues for neurodegeneration therapeutics.

Original languageEnglish (US)
Article number103396
JournalMolecular and Cellular Neuroscience
StatePublished - Oct 2019
Externally publishedYes


  • Alzheimer's disease
  • Amyotrophic lateral sclerosis
  • Frontotemporal dementia
  • Mitochondria
  • Neurodegeneration
  • Neurodegenerative diseases
  • TDP-43
  • TDP-43 proteinopathy

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology


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