
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.30.610586
preprint
1
Article
CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism
Liao Szu-Chi http://orcid.org/0000-0003-2744-363X

Kano Kohei http://orcid.org/0000-0002-0223-5781

Phanse Sadhna http://orcid.org/0000-0001-6306-0551

Nguyen Mai http://orcid.org/0000-0003-3550-7728

Margolis Elyssa http://orcid.org/0000-0001-8777-302X

Fu YuHong http://orcid.org/0000-0003-4539-2039

Meng Jonathan http://orcid.org/0000-0002-4315-3483

Moutaoufik Mohamed Taha http://orcid.org/0000-0002-2013-1601

Chatterton Zac http://orcid.org/0000-0002-6683-1400

Aoki Hiroyuki http://orcid.org/0009-0005-9143-086X

Simms Jeffrey
Hsieh Ivy
Suteja Felecia
Sei Yoshitaka http://orcid.org/0000-0002-4725-8725

Huang Eric J. http://orcid.org/0000-0002-5381-3801

McAvoy Kevin http://orcid.org/0000-0002-0025-1921

Manfredi Giovanni http://orcid.org/0000-0003-3893-1348

Halliday Glenda http://orcid.org/0000-0003-0422-8398

Babu Mohan http://orcid.org/0000-0003-4118-6406

Nakamura Ken http://orcid.org/0000-0002-9192-182X

31 8 2024
2024.08.30.610586https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.30.610586
nihpp-2024.08.30.610586.pdf
ABSTRACT

Mutations in the mitochondrial cristae protein CHCHD2 lead to a late-onset autosomal dominant form of Parkinson’s disease (PD) which closely resembles idiopathic PD, providing the opportunity to gain new insights into the mechanisms of mitochondrial dysfunction contributing to PD. To begin to address this, we used CRISPR genome-editing to generate CHCHD2 T61I point mutant mice. CHCHD2 T61I mice had normal viability, and had only subtle motor deficits with no signs of premature dopaminergic (DA) neuron degeneration. Nonetheless, CHCHD2 T61I mice exhibited robust molecular changes in the brain including increased CHCHD2 insolubility, accumulation of CHCHD2 protein preferentially in the substantia nigra (SN), and elevated levels of α-synuclein. Metabolic analyses revealed an increase in glucose metabolism through glycolysis relative to the TCA cycle with increased respiratory exchange ratio, and immune-electron microscopy revelated disrupted mitochondria in DA neurons. Moreover, spatial genomics revealed decreased expression of mitochondrial complex I and III respiratory chain proteins, while proteomics revealed increased respiratory chain and other mitochondrial protein-protein interactions. As such, the CHCHD2 T61I point-mutation mice exhibit robust mitochondrial disruption and a consequent metabolic shift towards glycolysis. These findings thus establish CHCHD2 T61I mice as a new model for mitochondrial-based PD, and implicate disrupted respiratory chain function as a likely causative driver.
==== Body
pmc
