Differential toxicity of TAR DNA-binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells

Illari Salvatori, Alberto Ferri, Silvia Scaricamazza, Ilaria Giovannelli, Alessia Serrano, Simona Rossi, Nadia D'Ambrosi, Mauro Cozzolino, Andrea Di Giulio, Sandra Moreno, Cristiana Valle, Maria Teresa Carrì

Research output: Contribution to journalArticlepeer-review


TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein and a major component of protein aggregates found in amyotrophic lateral sclerosis and several other neurodegenerative diseases. TDP-43 exists as a full-length protein and as two shorter forms of 25 and 35 kDa. Full-length mutant TDP-43s found in amyotrophic lateral sclerosis patients re-localize from the nucleus to the cytoplasm and in part to mitochondria, where they exert a toxic role associated with neurodegeneration. However, induction of mitochondrial damage by TDP-43 fragments is yet to be clarified. In this work, we show that the mitochondrial 35 kDa truncated form of TDP-43 is restricted to the intermembrane space, while the full-length forms also localize in the mitochondrial matrix in cultured neuronal NSC-34 cells. Interestingly, the full-length forms clearly affect mitochondrial metabolism and morphology, possibly via their ability to inhibit the expression of Complex I subunits encoded by the mitochondrial-transcribed mRNAs, while the 35 kDa form does not. In the light of the known differential contribution of the full-length and short isoforms to generate toxic aggregates, we propose that the presence of full-length TDP-43s in the matrix is a primary cause of mitochondrial damage. This in turn may cause oxidative stress inducing toxic oligomers formation, in which short TDP-43 forms play a major role. (Figure presented.).

Original languageEnglish
Pages (from-to)585-597
Number of pages13
JournalJournal of Neurochemistry
Issue number5
Publication statusPublished - Sep 1 2018


  • amyotrophic lateral sclerosis
  • Complex I
  • localization
  • mitochondria
  • neurodegeneration
  • TDP-43

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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