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.

Keywords: CHCHD10; CHCHD2; Lewy body disorders; Parkinson’s disease; mitochondria.

FIGURE 1

CHCHD2 amino acid sequence alignment and disease-associated mutations. Secondary structure and protein sequence alignment between human CHCHD2 and its homolog CHCHD10, along with their orthologs Caenorhabditis elegans har-1 and Drosophila CG5010. The amino acid positions of CHCHD2 disease-linked mutations are shown. The degree of conservation of affected residues in CHCHD2 versus homologous proteins are outlined in red (identical), purple (conserved), dashed purple (semi-conserved), and blue (not conserved).

FIGURE 2

Schematic of CHCHD2 functions in mitochondria and nucleus. (1) Precursor, reduced CHCHD2 is imported to the IMS of mitochondria via the TOM channel in a reduced state. Once CHCHD2 is imported, CHCHD2 interacts with oxidoreductase, Mia40. Mia40 redox-coupled, thiol-disulfide exchange system, inserts disulfide bonds into CHCHD2, and CHCHD2 is localized IMS. (2) Under conditions of hypoxic or oxidative stress, mitochondrial import of CHCHD2 is suppressed, allowing CHCHD2 to accumulate in the nucleus, where it acts as a transcription factor for cytochrome c oxidase (COX) subunit 4 isoform 2 (COX412) and CHCHD2 itself. (3) In the mitochondrial IMS, CHCHD2 binds to cytochrome c, MICS1, and COX to regulate COX activity (complex IV). Phosphorylation of CHCHD2 by Abl2 kinase increases its affinity for COX, resulting in increased respiratory activity. (4) CHCHD2 promotes mitochondrial unfolded protein response (UPRmt) and mitochondrial biogenesis by activating ATF5. (5) CHCHD2 competes with YME1L for binding to C1qBP, thereby decreasing OPA1 degradation by YME1L and promoting normal mitochondrial morphology. The binding of CHCHD2 to C1qBP also suppresses the anti-cell migration activity of C1qBP, therby enhancing cell migration. (6) CHCHD2 enhances the ability of Bcl-xL to suppress pro-apoptotic Bax oligomerization, thereby inhibiting cytochrome c release. (7) The sequestration of SMAD4 by CHCHD2 to mitochondria suppresses TGFB signaling, which primes hiPSCs toward neuroectodermal differentiation. (8) Finally, mitochondrial stress and loss of mitochondrial membrane potential increases CHCHD2/CHCHD10 heterodimerization and CHCHD2 is required for the oligomerization of CHCHD10. The physiological role of homo-hetero oligomers of CHCHD2 and CHCHD10 remains to be elucidated.