CHCHD2, short for coiled-coil-helix-coiled-coil-helix domain containing 2, is a mitochondrial protein. It is a bi-organellar mediator of oxidative phosphorylation, playing crucial roles in regulating electron flow in the mitochondrial electron transport chain. It also acts as a nuclear transcription factor for a cytochrome c oxidase subunit (COX4I2) and itself in response to hypoxic stress. Additionally, CHCHD2 is involved in regulating cell migration, differentiation, mitochondrial cristae structure, and apoptosis [2].

Mutations in CHCHD2 have been identified in various neurological diseases such as Parkinson's disease (PD), frontotemporal dementia (FTD), and Alzheimer's disease (AD). It is the first mitochondrial gene whose mutations lead to PD [1]. Multiple experimental models suggest that CHCHD2 maintains mitochondrial cristae and disease-associated CHCHD2 mutations function in a loss-of-function manner. However, both CHCHD2 knockout mouse models appear phenotypically normal, with no obvious mitochondrial defects [1]. CHCHD2 T61I point-mutation mice, generated using CRISPR genome-editing, exhibit robust mitochondrial disruption and a consequent metabolic shift towards glycolysis, with increased glucose metabolism through glycolysis relative to the TCA cycle, elevated α-synuclein levels, and disrupted mitochondria in DA neurons [3].

In conclusion, CHCHD2 is essential for mitochondrial function, especially in maintaining mitochondrial cristae and regulating energy metabolism. The study of CHCHD2 knockout and mutant mouse models has provided insights into its role in neurodegenerative diseases, particularly PD, highlighting its potential as a therapeutic target for these neurological conditions.

References:

1. Zhou, Wei, Ma, Dongrui, Tan, Eng-King. 2019. Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications. In The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry, 26, 170-184. doi:10.1177/1073858419871214. https://pubmed.ncbi.nlm.nih.gov/31526091/

2. Kee, Teresa R, Espinoza Gonzalez, Pamela, Wehinger, Jessica L, Kang, David E, Woo, Jung-A A. 2021. Mitochondrial CHCHD2: Disease-Associated Mutations, Physiological Functions, and Current Animal Models. In Frontiers in aging neuroscience, 13, 660843. doi:10.3389/fnagi.2021.660843. https://pubmed.ncbi.nlm.nih.gov/33967741/

3. Liao, Szu-Chi, Kano, Kohei, Phanse, Sadhna, Babu, Mohan, Nakamura, Ken. 2024. CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.08.30.610586. https://pubmed.ncbi.nlm.nih.gov/39257750/