Loss of Parkinson’s disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c

Abstract

Mutations in CHCHD2 have been identified in some Parkinson's disease (PD) cases. To understand the physiological and pathological roles of CHCHD2, we manipulated the expression of CHCHD2 in Drosophila and mammalian cells. The loss of CHCHD2 in Drosophila causes abnormal matrix structures and impaired oxygen respiration in mitochondria, leading to oxidative stress, dopaminergic neuron loss and motor dysfunction with age. These PD-associated phenotypes are rescued by the overexpression of the translation inhibitor 4E-BP and by the introduction of human CHCHD2 but not its PD-associated mutants. CHCHD2 is upregulated by various mitochondrial stresses, including the destabilization of mitochondrial genomes and unfolded protein stress, in Drosophila. CHCHD2 binds to cytochrome c along with a member of the Bax inhibitor-1 superfamily, MICS1, and modulated cell death signalling, suggesting that CHCHD2 dynamically regulates the functions of cytochrome c in both oxidative phosphorylation and cell death in response to mitochondrial stress.

Respiratory supercomplexes act as a platform for complex III ‐mediated maturation of human mitochondrial complexes I and IV

“…The amounts of nine known cI assembly factors (ACAD9, ECSIT, FOXRED1, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF6, and TMEM126B) did not differ significantly between the D4-CYB and WT cells (Fig 2A). GHITM localizes to the inner mitochondrial membrane, interacts with CHCHD2, and is deemed to participate in the maintenance of mitochondrial morphology and integrity (Oka et al, 2008;Meng et al, 2017). Other proteins were also upregulated in the mutant cells.…”

“…These included CHCHD2, whose knock-down causes cIV deficiency (Baughman et al, 2009;Imai et al, 2019), HIGD2A, one of the human orthologs of yeast Rcf1, which stabilizes the interaction between cIII 2 and cIV (Chen et al, 2012;Strogolova et al, 2012;Vukotic et al, 2012;Rieger et al, 2017), and GHITM or growth hormone-inducible transmembrane protein, a member of the BAX inhibitor motif-containing (TMBIM) family. GHITM localizes to the inner mitochondrial membrane, interacts with CHCHD2, and is deemed to participate in the maintenance of mitochondrial morphology and integrity (Oka et al, 2008;Meng et al, 2017).…”

Monitoring α‐synuclein multimerization in vivo

“…However, rotenone-treated flies displayed a ;1.5-fold increase in the abundance of insoluble a-Syn aggregates. Rotenone treatment in flies causes an increase in ROS as a secondary effect of complex I inhibition (63)(64)(65)(66)(67). Thus, we assessed the effect of the general ROS-inducer H 2 O 2 on a-Syn aggregation.…”

Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1

“…If C2C10H S81L is a dominant-negative mutant that suppresses C2C10H WT activity, the C2C10H deletion mutant (C2C10H null ) phenotype will not be enhanced by C2CH10 S59L . Because C2C10H null flies do not exhibit an abnormal eye phenotype and are generally healthy (35), we hypothesized that the C2C10H S81L -induced rough eye phenotype would not occur in the C2CH10H null background. However, the rough eye phenotype was robust without C2C10H WT expression ( fig.…”