CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology

Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil-helix-coiled-coil-helix domain-containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced mitochondrial disruption in substantia nigra dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift toward glycolysis, elevated mitochondrial reactive oxygen species (ROS), and progressive accumulation of aggregated α-synuclein. In idiopathic PD, <i>CHCHD2</i> gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.

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Publication Details

Journal
Science Advances
Published
2025-11-14
DOI
https://doi.org/10.1126/sciadv.adu0726
Citations
2
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
2.78
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article

CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology

Elyssa B. Margolis, Kirsten Broderick, Mohamed Taha Moutaoufik, YuHong Fu et al.
2 citations
Science Advances
Parkinson's Disease Mechanisms and Treatments
2.78
article

CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology

Elyssa B. Margolis, Kirsten Broderick, Mohamed Taha Moutaoufik, YuHong Fu, Eric J. Huang, Tatiana D. Saccon, Zac Chatterton, Glenda Margaret Halliday, Mai K. Nguyen, Felicia Suteja, Sadhna Phanse, Giovanni Manfredi, Mohan Babu, Szu-Chi Liao, Kevin McAvoy, Ken Nakamura, Yoshitaka Sei, Kohei Kano, Jonathan X. Meng, H Aoki, Jeffrey A. Simms
article en
2 citations

Abstract

Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil-helix-coiled-coil-helix domain-containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced mitochondrial disruption in substantia nigra dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift toward glycolysis, elevated mitochondrial reactive oxygen species (ROS), and progressive accumulation of aggregated α-synuclein. In idiopathic PD, <i>CHCHD2</i> gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.

Science AdvancesVol. 11(46)
The University of Sydney (AU), Gladstone Institutes (US), University of California, San Francisco (US), University of Regina (CA), Cornell University (US), MIND Research Institute (US), Center for Neurosciences (US), Université Mohammed VI Polytechnique (MA), Research Network (United States) (US), Weill Cornell Medicine (US), University of California, Berkeley (US)
Openalex Percentile: Top 8%
Parkinson's Disease Mechanisms and Treatments
2.78
DOIOpen Access PDFOpenAlex
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