PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction

Abstract

Coiled-coil-helix-coiled-coil-helix domain containing protein 2 (CHCHD2) mutations were linked with autosomal dominant Parkinson’s disease (PD) and recently, Alzheimer’s disease/frontotemporal dementia. In the current study, we generated isogenic human embryonic stem cell (hESC) lines harboring PD-associated CHCHD2 mutation R145Q or Q126X via clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) method, aiming to unravel pathophysiologic mechanism and seek potential intervention strategy against CHCHD2 mutant-caused defects. By engaging super-resolution microscopy, we identified a physical proximity and similar distribution pattern of CHCHD2 along mitochondria with mitochondrial contact site and cristae organizing system (MICOS), a large protein complex maintaining mitochondria cristae. Isogenic hESCs and differentiated neural progenitor cells (NPCs) harboring CHCHD2 R145Q or Q126X mutation showed impaired mitochondria function, reduced CHCHD2 and MICOS components and exhibited nearly hollow mitochondria with reduced cristae. Furthermore, PD-linked CHCHD2 mutations lost their interaction with coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10), while transient knockdown of either CHCHD2 or CHCHD10 reduced MICOS and mitochondria cristae. Importantly, a specific mitochondria-targeted peptide, Elamipretide/MTP-131, now tested in phase 3 clinical trials for mitochondrial diseases, was found to enhance CHCHD2 with MICOS and mitochondria oxidative phosphorylation enzymes in isogenic NPCs harboring heterozygous R145Q, suggesting that Elamipretide is able to attenuate CHCHD2 R145Q-induced mitochondria dysfunction. Taken together, our results suggested CHCHD2–CHCHD10 complex may be a novel therapeutic target for PD and related neurodegenerative disorders, and Elamipretide may benefit CHCHD2 mutation-linked PD.

Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice

“…Here, we showed that CHCHD10 is significantly reduced in ALS spinal cord tissues, suggesting that there is a loss of CHCHD10 function at least at the end stage of the disease. This reduction of CHCHD10 may lead to MICOS reduction, abnormal mitochondrial cristae structure and synaptic damage leading to motor neuron death 23 48. It is also worth noting that while CHCHD10 protein expression levels were significantly higher for control samples than ALS cases, there was considerable variation, particularly among control samples (figure 3B and supplementary table 2).…”

AIDS tedavisi için gen düzenleme çalışmaları

“…Although CRISPR mediated treatment systems are widely used in both mentioned fatal diseases that are caused by SNPs or in other dangerous and deadly diseases like Parkinson's disease (PD) (Zhou, et al 2018), Duchenne muscular dystrophy (DMD) (Lim, et al 2018) or various cardiovascular diseases, they do have their downsides and limitations that require additional work and research to overcome them.…”

Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations in vivo

“…As the MICOS complex is reported to interact with OPA1 and with C2/C10 (Ding et al, 2015;Darshi et al, 2011;Genin et al, 2016;Zhou et al, 2019), we tested whether reduction in MICOS subunits could account for the observed OMA1 activation and L-OPA1 cleavage. As expected, depletion of a central subunit of the MICOS complex, MIC60, destabilized MIC19 and MIC27, components of the respective MICOS subcomplexes ( Figure 2D).…”

“…Although their precise function remains unknown, cristae abnormalities have been observed in muscle tissue and cell lines from patients with C10 mutations, as well as a Drosophila lacking the C2/C10 ortholog (Bannwarth et al, 2014;Ajroud-Driss et al, 2015;Meng et al, 2017). To explain cristae abnormalities in C2/C10 patients, C10 and later C2 were proposed to be structural components of the mitochondrial contact site and cristae organizing system (MICOS) complex (Bannwarth et al, 2014;Genin et al, 2016;Zhou et al, 2019). However, recent reports have challenged this model, suggesting that C2/C10 mutation or loss may lead to cristae abnormalities by another as of yet unidentified mechanism (Straub et al, 2018;Burstein et al, 2018;Huang et al, 2018).…”