A novel CHCHD10 mutation implicates a Mia40-dependent mitochondrial import deficit in ALS pathogenesis Carina Lehmer1 Martin H. Schludi1, Linnea Ransom1, Johanna Greiling1, Michaela Junghänel1, Nicole Exner2, Julie van der Zee4, Christine van Broeckhoven4, Patrick Weydt3, Michael T. Heneka3, Dieter Edbauer1,2 1German Center for Neurodegenerative Diseases Munich, Germany; 2Biomedical Center, Ludwig-Maximilians-Universität Munich, Germany; 3Department of Neurodegenerative Diseases and Gerontopsychiatry, Bonn University Hospital, Germany; 4VIB Center for Molecular Neurology, University of Antwerp, Belgium
Mutations in CHCHD10 have been linked to amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and mitochondrial myopathy. CHCHD10 is a small mitochondrial protein and consists of three domains including a putative N-terminal mitochondrial targeting sequence (MTS), a hydrophobic helix and a coiled-coil-helix-coiled-coil-helix (CHCH) domain. We discovered a novel CHCHD10 mutation (Q108P) in a 29-year old ALS patient with rapid disease progression. While most known pathogenic mutations are located around the putative MTS or hydrophobic region, Q108P is in a highly conserved residue within the CHCH domain. To elucidate underlying pathomechanisms, we analyzed known and newly discovered ALS-causing CHCHD10 mutations in vitro. Interestingly, mutations in the CHCH domain showed the biggest effect on mitochondrial import, mainly resulting in diffuse cytoplasmic localization. Deletion experiments further supported our hypothesis that mitochondrial import of CHCHD10 is predominantly mediated by the CHCH domain rather than the putative MTS. Mia40 has been implicated in the mitochondrial import of small intermembrane space proteins by introducing disulfide bonds in CHCH domains and thereby stabilizing its substrates. Strikingly, in CHCHD10 Q108P both disulfide bond formation and protein stability was reduced. Knock down of Mia40, decreased overall CHCHD10 level, whereas overexpressed Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide bond formation and increasing protein stability. Interestingly, CHCHD10 knockdown in HeLa or HAP1 cell lines and patient derived Q108* lymphoblastoid cells showed reduced respiratory spare capacity. Thus, discovery of the Q108P mutation supports a loss-of-function component for CHCHD10-mediated ALS/FTD through impaired respiration. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway.
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