CHCHD 10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis

Abstract

CHCHD10‐related diseases include mitochondrial DNA instability disorder, frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS) clinical spectrum, late‐onset spinal motor neuropathy (SMAJ), and Charcot–Marie–Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the “mitochondrial contact site and cristae organizing system” (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release.

Disrupted in schizophrenia 1 (DISC1) is a constituent of the mammalian mitochondrial contact site and cristae organizing system (MICOS) complex, and is essential for oxidative phosphorylation

“…Aligning with our observed results, long-term depletion of SAM50, a core component of the SAM complex, or Mic60/Mitofilin translate into down-regulation of OXPHOS proteins and impacts on the assembly of the respiratory complexes and the maintenance of the mtDNA (39). The MIB/MICOS complex also plays an important role in nucleoid organization (40), and defects in MICOS subunits translate in nucleoid disorganization, leading to mtDNA damage after oxidative stress (16). DISC1 KD cells displayed a significant depletion of mtDNA that could also account for the decreased steady-state levels of COXI, observed in DISC1 KD cells.…”

“…To verify that mdisc1-containing complex was MICOS, we performed two dimensional western-blotting (2D-WB) of the BN-PAGE, to separate the individual subunits of MICOS. By sequentially immunoblotting with the different MICOS subunits antibodies, we observed that mdisc1 immunoreactive band aligned with the known MICOS subunits Mic60/Mitofilin, Mic19/ CHCHD3 and Mic25/CHCHD6 and with the recently reported novel MICOS subunit CHCHD10 (16) (Fig. 2C).…”

“…Error bars represent 6 SD of three independent experiments. * P < 0.05; ** P < 0.01. molecular weight of these subunits is $200 kDa; however, others and we have identified the mammalian MICOS at $700 kDa migration band in native gels (16,30), suggesting that there are novel subunits that remain to be identified. Among these ones, QIL1/C19orf70 (30) has been recently identified, shown to be the mammalian ortholog of Mic12 (31), and we recently identified CHCHD10 as a novel subunit of MICOS (16).…”

“…Since MICOS alterations have been associated with deficits in mitochondrial biogenesis and mitochondrial DNA (mtDNA) instability (16,17,25,26), we investigated whether hDISC1 depletion in SH-SY5Y cells affects mtDNA levels and OXPHOS proteins steady-state levels. Total mtDNA content was decreased by 20% 6 6.8 (P < 0.05) in hDISC1 KD cells (Fig.…”

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

“…Most studies have focused on characterizing CHCHD10's effects in mitochondria by testing the effects of pathogenic mutations in a cell culture system (8,9,14). These studies have suggested that CHCHD10 affects stability of mitochondrial cristae (9, 14), COX activity (7), formation of mitochondrial networks (8), stability of mitochondrial DNA, and apoptosis (14).Here, we demonstrate that CHCHD10, like MNRR1, is a hypoxia-responsive gene whose product functions in both the mitochondria and the nucleus. In the mitochondria, CHCHD10 also interacts with COX and stimulates oxygen consumption.…”