Abstract
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.
Highlights
The recent identification of mutations in CHCHD10 implicates mitochondrial dysfunction in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (Bannwarth et al, 2014)
Electron microscopy and biochemical studies suggest that CHCHD10 resides in the mitochondrial contact site and cristae organizing system (MICOS) in the intermembrane space of mitochondria (Bannwarth et al, 2014) that has been recently disputed by others (Burstein et al, 2018)
We show that the Q108P mutation blocks mitochondrial import nearly completely, and examine the mechanism of CHCHD10 mitochondrial import in detail, including rescue strategies
Summary
The recent identification of mutations in CHCHD10 implicates mitochondrial dysfunction in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (Bannwarth et al, 2014). CHCHD10 is a small soluble protein with a positively charged N-terminus commonly referred to as a mitochondrial targeting signal (MTS), a central hydrophobic domain and a C-terminal CHCH domain (Perrone et al, 2017). Mutations have been reported mainly in the N-terminus and the central hydrophobic domain. Electron microscopy and biochemical studies suggest that CHCHD10 resides in the mitochondrial contact site and cristae organizing system (MICOS) in the intermembrane space of mitochondria (Bannwarth et al, 2014) that has been recently disputed by others (Burstein et al, 2018). In the MICOS complex, CHCHD10 interacts with mitofusin, CHCHD3, and CHCHD6 and it seems to be required for proper packaging of mitochondrial DNA into the nucleoid structures (Genin et al, 2016)
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