CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis.
CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis.
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DOI：
10.15252/emmm.201505496
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发表时间：
2016-01-01
影响因子：
11.1
通讯作者：
Paquis-Flucklinger V
中科院分区：
文献类型：
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作者：
Genin EC;Plutino M;Bannwarth S;Villa E;Cisneros-Barroso E;Roy M;Ortega-Vila B;Fragaki K;Lespinasse F;Pinero-Martos E;Augé G;Moore D;Burté F;Lacas-Gervais S;Kageyama Y;Itoh K;Yu-Wai-Man P;Sesaki H;Ricci JE;Vives-Bauza C;Paquis-Flucklinger V
CHCHD 10相关疾病包括线粒体DNA不稳定性疾病、额颞叶痴呆-肌萎缩侧索硬化（FTD-ALS）临床谱、迟发性脊髓运动神经病（SMAJ）和2型腓骨肌萎缩症（CMT 2）。在这里，我们表明，CHCHD 10居住与丝裂素，CHCHD 3和CHCHD 6内的“线粒体接触位点和嵴组织系统”（MICOS）复杂。CHCHD 10突变导致MICOS复合体解体和线粒体嵴丢失，伴随着类核数目减少和类核解体。在CHCHD 10突变成纤维细胞中，氧化应激后线粒体基因组的修复受损，这可能解释了患者肌肉中缺失的mtDNA分子的积累。CHCHD 10突变体成纤维细胞在将线粒体递送至溶酶体方面没有缺陷，这表明受损的线粒体自噬不会导致mtDNA不稳定。有趣的是，CHCHD 10突变等位基因的表达通过阻止细胞色素c释放来抑制细胞凋亡。
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.