Mitochondrial CHCHD2: Disease-Associated Mutations, Physiological Functions, and Current Animal Models

Abstract

Rare mutations in the mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) are associated with Parkinson’s disease (PD) and other Lewy body disorders. CHCHD2 is a bi-organellar mediator of oxidative phosphorylation, playing crucial roles in regulating electron flow in the mitochondrial electron transport chain and acting as a nuclear transcription factor for a cytochrome c oxidase subunit (COX4I2) and itself in response to hypoxic stress. CHCHD2 also regulates cell migration and differentiation, mitochondrial cristae structure, and apoptosis. In this review, we summarize the known disease-associated mutations of CHCHD2 in Asian and Caucasian populations, the physiological functions of CHCHD2, how CHCHD2 mutations contribute to α-synuclein pathology, and current animal models of CHCHD2. Further, we discuss the necessity of continued investigation into the divergent functions of CHCHD2 and CHCHD10 to determine how mutations in these similar mitochondrial proteins contribute to different neurodegenerative diseases.

Molecular convergence between Down syndrome and fragile X syndrome identified using human pluripotent stem cell models

“…Article ll OPEN ACCESS in both the DS hPSC dataset (p = 4.96 3 10 À134 ) and the FXS hPSC dataset (p = 3.68 3 10 À52 ), with dramatic downregulation observed in both disease models (Figures 3B and 2F; Tables S3 and S4). Rare mutations in CHCHD2 have been associated with several neurodegenerative diseases (Kee et al, 2021) and we noted that CHCHD2 expression levels continued to be dramatically downregulated in DS neurons, but not in FXS neurons (Tables S3 and S4). Other genes of note that were coordinately dysregulated included the protein glycosylation factor tumor suppressor candidate 3 (TUSC3), the putative magnesium transporter NIPA magnesium transporter 2 (NIPA2), the transcriptional regulator SRY-box transcription factor 11 (SOX11), and the alternative splicing regulator NOVA alternative splicing regulator 2 (NOVA2) (Figure 3B; Tables S3 and S4), all of which have been independently implicated in neurodevelopmental disorders (Garshasbi et al, 2008;Mattioli et al, 2020;Tsurusaki et al, 2014;Xie et al, 2014).…”

“…The most significantly DEGs in our DS datasets were not genes encoded on HSA21. The mitochondrial and transcriptional regulator coiled-coil-helix-coiled-coil-helix domain containing 2 ( CHCHD2 ), which is a key mediator of the oxidative phosphorylation process ( Kee et al, 2021 ) and is encoded on chromosome 7, was the most significant DEG in our DS hPSC dataset, while the proteolipid neuronatin ( NNAT ) implicated in synaptic plasticity ( Joseph, 2014 ) and encoded on chromosome 20, was the most significant DEG in our DS neuron dataset ( Figure 2F ; Table S3 ). These examples highlight the striking indirect effects of HSA21 triplication, and the challenge in identifying all potentially relevant gene perturbations.…”

Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan–Kynurenine Metabolic System

“…The Parkin KO mouse is a classic transgenic PD model, while there are few studies using DJ-1 KO rats [ 199 ]. Homozygous CHCHD2 KO mice mimic PD pathology in an age-dependent manner; they are indistinguishable at birth, but fragmented mitochondria in dopaminergic neurons compared to the wild type [ 200 ]. NADH ubiquinone oxidoreductase core subunit S2 (NDUFS2) is a subunit of complex I in neurons that produce dopamine.…”

Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan-Kynurenine Metabolic System

“…The Parkin knockout mouse is a classic transgenic PD model, while there are few studies using DJ-1 knockout rats [180]. Homozygous CHCHD2 knockout mice mimic PD pathology in an age-dependent manner: indistinguishable at birth, but fragmented mitochondria in dopaminergic neurons compared to the wild type [181]. NADH:Ubiquinone Oxidoreductase Core Subunit S2 (NDUFS2) is a subunit of complex I in neurons that produce dopamine.…”