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Differential toxicity of TAR DNA‐binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells
Author(s) -
Salvatori Illari,
Ferri Alberto,
Scaricamazza Silvia,
Giovannelli Ilaria,
Serrano Alessia,
Rossi Simona,
D'Ambrosi Nadia,
Cozzolino Mauro,
Giulio Andrea Di,
Moreno Sandra,
Valle Cristiana,
Carrì Maria Teresa
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14465
Subject(s) - mitochondrial intermembrane space , neurodegeneration , mitochondrion , microbiology and biotechnology , biology , cytoplasm , gene isoform , stress granule , submitochondrial particle , translation (biology) , biochemistry , messenger rna , gene , bacterial outer membrane , medicine , disease , escherichia coli , pathology
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 kD a. 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 kD a 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 mRNA s, while the 35 kD a 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.