Abstract
Mutations in CHCHD2 have been identified in some Parkinson’s disease (PD) cases. To understand the physiological and pathological roles of CHCHD2, we manipulated the expression of CHCHD2 in Drosophila and mammalian cells. The loss of CHCHD2 in Drosophila causes abnormal matrix structures and impaired oxygen respiration in mitochondria, leading to oxidative stress, dopaminergic neuron loss and motor dysfunction with age. These PD-associated phenotypes are rescued by the overexpression of the translation inhibitor 4E-BP and by the introduction of human CHCHD2 but not its PD-associated mutants. CHCHD2 is upregulated by various mitochondrial stresses, including the destabilization of mitochondrial genomes and unfolded protein stress, in Drosophila. CHCHD2 binds to cytochrome c along with a member of the Bax inhibitor-1 superfamily, MICS1, and modulated cell death signalling, suggesting that CHCHD2 dynamically regulates the functions of cytochrome c in both oxidative phosphorylation and cell death in response to mitochondrial stress.
Highlights
Mutations in CHCHD2 have been identified in some Parkinson’s disease (PD) cases
CHCHD2 orthologs are present in various species, including worm, yeast, and plants, and the affected amino acids found in PD cases are mildly conserved among these species (Supplementary Fig. 1a)[5]
Similar results were obtained with 14-day-old dCHCHD2 À / À flies (Supplementary Movies 1 and 2), and the disintegration of the mitochondrial cristae progressed in 40-day-old flies (Fig. 1c–e)
Summary
Mutations in CHCHD2 have been identified in some Parkinson’s disease (PD) cases. To understand the physiological and pathological roles of CHCHD2, we manipulated the expression of CHCHD2 in Drosophila and mammalian cells. The loss of CHCHD2 in Drosophila causes abnormal matrix structures and impaired oxygen respiration in mitochondria, leading to oxidative stress, dopaminergic neuron loss and motor dysfunction with age. These PD-associated phenotypes are rescued by the overexpression of the translation inhibitor 4E-BP and by the introduction of human CHCHD2 but not its PD-associated mutants. We report that the loss of CHCHD2 in flies leads to mitochondrial and neuronal phenotypes associated with PD pathology, including increased sensitivity to oxidative stress and loss of dopaminergic (DA) neurons with age These phenotypes are rescued by 4E-BP and human CHCHD2 but not by CHCHD2 mutants found in PD cases. Our study suggests that mutations of CHCHD2 have a loss-of-function aspect in PD, exacerbating oxidative stress and cell death signalling
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