Details

Autor(en) / Beteiligte

• Lehmer, Carina
• Schludi, Martin H
• Ransom, Linnea
• Greiling, Johanna
• Junghänel, Michaela
• Exner, Nicole
• Riemenschneider, Henrick
• Zee, Julie
• Van Broeckhoven, Christine
• Weydt, Patrick
• Heneka, Michael T
• Edbauer, Dieter

Titel

A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

Ist Teil von

• EMBO molecular medicine, 2018-06, Vol.10 (6), p.n/a

Ort / Verlag

England: John Wiley & Sons, Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• CHCHD10 mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29‐year‐old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled‐coil‐helix‐coiled‐coil‐helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild‐type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability. Other CHCHD10 variants reported in patients showed impaired mitochondrial import (C122R) or clustering within mitochondria (especially G66V and E127K) often associated with reduced expression. Truncation experiments suggest mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the proposed N‐terminal mitochondrial targeting signal. Knockdown of Mia40, which introduces disulfide bonds into CHCH domain proteins, blocked mitochondrial import of CHCHD10. Overexpression of Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide‐bond formation. Since reduction in CHCHD10 inhibits respiration, mutations in its CHCH domain may cause aggressive disease by impairing mitochondrial import. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway. Synopsis Mutations in the mitochondrial protein CHCHD10 have been linked to amyotrophic lateral sclerosis, but incomplete penetrance has raised concerns about pathogenicity. The identification of a novel mutation (Q108P) in a young patient with aggressive disease reveals a loss‐of‐function mechanism. CHCHD10 Q108P disrupts mitochondrial import resulting in reduced protein half‐life time. CHCHD10 reduction results in smaller spare respiratory capacity. Mia40 imports CHCHD10 into mitochondria through disulfide‐bond formation in the CHCH domain. Overexpression of Mia40 restores mitochondrial targeting of CHCHD10 Q108P. Mutations in the mitochondrial protein CHCHD10 have been linked to amyotrophic lateral sclerosis, but incomplete penetrance has raised concerns about pathogenicity. The identification of a novel mutation (Q108P) in a young patient with aggressive disease reveals a loss‐of‐function mechanism.