Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism - UTU Research Portal

A1 Refereed original research article in a scientific journal

Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism

Authors: Harjuhaahto, Sandra; Jokela, Manu; Rajendran, Jayasimman; Rokka, Minea; Hu, Bowen; Kvist, Jouni; Zhang, Fuping; Zárybnický, Tomáš; Haimilahti, Kimmo; Euro, Liliya; Pirinen, Eija; Huber, Nadine; Herukka, Sanna-Kaisa; Haapasalo, Annakaisa; Kuuluvainen, Emilia; Gopalakrishnan, Swetha; Katajisto, Pekka; Hietakangas, Ville; Burg, Thibaut; Van Den Bosch, Ludo; Huang, Xiaoping; Narendra, Derek P.; Kuure, Satu; Ylikallio, Emil; Tyynismaa, Henna

Publisher: BMC

Publishing place: LONDON

Publication year: 2025

Journal: Acta Neuropathologica Communications

Journal name in source: ACTA NEUROPATHOLOGICA COMMUNICATIONS

Journal acronym: ACTA NEUROPATHOL COM

Article number: 111

Volume: 13

Issue: 1

Number of pages: 21

eISSN: 2051-5960

DOI: https://doi.org/10.1186/s40478-025-02039-3(external)

Web address : https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-025-02039-3(external)

Abstract

Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant are less clear. Here we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ. We demonstrate that the amount of the mutant CHCHD10 is reduced, but the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state. Novel knock-in mouse model recapitulates the dose-dependent reduction of mutant CHCHD10 protein and the slow disease progression of SMAJ. With metabolome analysis of patients' primary fibroblasts and patient-specific motor neurons, we show that CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.

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Funding information in the publication:
Open Access funding provided by University of Helsinki (including Helsinki University Central Hospital).
This study has been funded by the Research Council of Finland Centre of Excellence on Stem Cell Metabolism, Sigrid Juselius Foundation, Magnus Ehrnrooth Foundation, Emil Aaltonen Foundation, Orion Research Foundation, Biomedicum Helsinki Foundation, Päivikki and Sakari Sohlberg Foundation, Paulo Foundation, Finnish-Norwegian Medicine Foundation, University of Helsinki, and Helsinki University Hospital.