Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS‐like phenotype and Complex I deficiency independent of the mitochondrial integrated stress response

Abstract

Mutations in CHCHD10 and CHCHD2, encoding two paralogous mitochondrial proteins, have been identified in cases of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Parkinson's disease. Their role in disease is unclear, though both have been linked to mitochondrial respiration and mitochondrial stress responses. Here, we investigated the biological roles of these proteins during vertebrate development using knockout (KO) models in zebrafish. We demonstrate that loss of either or both proteins leads to motor impairment, reduced survival and compromised neuromuscular junction integrity in larval zebrafish. Compensation by Chchd10 was observed in the chchd2−/− model, but not by Chchd2 in the chchd10−/− model. The assembly of mitochondrial respiratory chain Complex I was impaired in chchd10−/− and chchd2−/− zebrafish larvae, but unexpectedly not in a double chchd10−/− and chchd2−/− model, suggesting that reduced mitochondrial Complex I cannot be solely responsible for the observed phenotypes, which are generally more severe in the double KO. We observed transcriptional activation markers of the mitochondrial integrated stress response (mt‐ISR) in the double chchd10−/− and chchd2−/− KO model, suggesting that this pathway is involved in the restoration of Complex I assembly in our double KO model. The data presented here demonstrates that the Complex I assembly defect in our single KO models arises independently of the mt‐ISR. Furthermore, this study provides evidence that both proteins are required for normal vertebrate development.

Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease

“…Other animal models of CHCHD10 demonstrate further evidence of motor deficits, reduced survival, and NMJ abnormalities [79][80][81]. In line with the association of CHCHD10 with neurodegenerative disease such as ALS, a mouse model expressing a patient mutation in CHCHD10 displayed progressive NMJ degeneration, including motor neuron loss [80].…”

“…In line with the association of CHCHD10 with neurodegenerative disease such as ALS, a mouse model expressing a patient mutation in CHCHD10 displayed progressive NMJ degeneration, including motor neuron loss [80]. Animal models have also demonstrated the deficient activity, assembly, and expression of numerous respiratory chain complexes [80,81]. These results provide a partial explanation as to why ATP production at the NMJ is impacted by CHCHD10 mutations; however, the mechanism is not yet fully elucidated.…”

Modeling familial and sporadic Parkinson's disease in small fishes

“…Comparable PD‐associated phenotypes manifest in transgenic mice expressing human CHCHD2 T61I (Kee et al, 2022). In zebrafish, chchd2 knockout results in deficiency in mitochondrial complex I and locomotion defects (Petel Légaré et al, 2023). Additional deletion of the closely related homolog chchd10 exacerbates these phenotypes (Petel Légaré et al, 2023).…”

“…In zebrafish, chchd2 knockout results in deficiency in mitochondrial complex I and locomotion defects (Petel Légaré et al, 2023). Additional deletion of the closely related homolog chchd10 exacerbates these phenotypes (Petel Légaré et al, 2023). While the presence of PD‐related pathologies necessitates validation within these zebrafish lines, these observations collectively imply the phenomenon of negative dominance arising from the Chchd2 mutation in both murine and zebrafish models.…”