Systematic analysis of a mitochondrial disease‐causing <i>ND6</i> mutation in mitochondrial deficiency

Chen, Deyu; Zhao, Qiongya; Xiong, Jingting; Lou, Xiaoting; Han, Qinxia; Wei, Xiujuan; Xie, Jun; Xu, Tongwen; Zhou, Huaibin; Shen, Lijun; Yang, Yanling; Fang, Hezhi; Lyu, Jianxin

doi:10.1002/mgg3.1199

Cited by 6 publications

(2 citation statements)

References 65 publications

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“…Whether mitochondria are involved in ferroptosis is so far still controversial. 38 , 39 , 40 To address this question, we used osteosarcoma 143B RHO° cells (cells lacking mitochondrial DNA) and parental 143B cells (Figure 4D and 41 ). Similar to overexpressing RB1CC1 conditions, overexpressing CHCHD3 also sensitised 143B cells to ferroptosis, but such effects were diminished in 143B RHO° cells (Figure 4E ), suggesting that mitochondria are at least essential for RB1CC1 and CHCHD3 to sensitise ferroptosis.…”

Section: Resultsmentioning

confidence: 99%

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

Xue

Zhang

et al. 2022

Clinical & Translational Med

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Background Ferroptosis, a form of regulated cell death, is an important topic in the field of cancer research. However, the signalling pathways and factors that sensitise tumour cells to ferroptosis remain elusive. Methods We determined the level of ferroptosis in cells by measuring cell death and lipid reactive oxygen species (ROS) production. The expression of RB1‐inducible coiled‐coil 1 (RB1CC1) and related proteins was analyzed by immunoblotting and immunohistochemistry. Immunofluorescence was used to determine the subcellular localization of RB1CC1. We investigated the mechanism of RB1CC1 nuclear translocation by constructing a series of RB1CC1 variants. To examine the ferroptosis‐ and RB1CC1‐dependent transcriptional program in tumour cells, chromatin immunoprecipitation sequencing was performed. To assess the effect of c‐Jun N‐terminal kinase (JNK) agonists on strenthening imidazole ketone erastin (IKE) therapy, we constructed cell‐derived xenograft mouse models. Mouse models of hepatocellular carcinoma to elucidate the importance of Rb1cc1 in IKE‐based therapy of liver tumourigenesis. Results RB1CC1 is upregulated by lipid ROS and that nuclear translocation of phosphorylation of RB1CC1 at Ser537 was essential for sensitising ferroptosis in tumour cells. Upon ferroptosis induction, nuclear RB1CC1 sharing forkhead box (FOX)‐binding motifs recruits elongator acetyltransferase complex subunit 3 (ELP3) to strengthen H4K12Ac histone modifications within enhancers linked to ferroptosis. This also stimulated transcription of ferroptosis‐associated genes, such as coiled‐coil–helix–coiled‐coil–helix domain containing 3 (CHCHD3), which enhanced mitochondrial function to elevate mitochondrial ROS early following induction of ferroptosis. FDA‐approved JNK activators reinforced RB1CC1 nuclear translocation and sensitised cells to ferroptosis, which strongly suggested that JNK is upstream of RB1CC1. Nuclear localisation of RB1CC1 correlated with lipid peroxidation in clinical lung cancer specimens. Rb1cc1 was essential for ferroptosis agonists to suppress liver tumourigenesis in mice. Conclusions Our findings indicate that RB1CC1‐associated signalling sensitises tumour cells to ferroptosis and that targeting RB1CC1 may be beneficial for tumour treatment.

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Section: Resultsmentioning

confidence: 99%

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

Xue

Zhang

et al. 2022

Clinical & Translational Med

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“…In brief, 500 ng of RNA was used with a reverse transcription kit (Takara, Kusatsu, Shiga, Japan). Then, fluorogenic SYBR Green (Bio-Rad, Hercules, CA, USA) was used for qPCR, following the protocol suggested previously [ 39 ]. The primers for the qPCR amplification are listed in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial tRNAGln 4394C>T Mutation May Contribute to the Clinical Expression of 1555A>G-Induced Deafness

Ding

Teng

Guo

et al. 2022

Genes

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The mitochondrial 1555A>G mutation plays a critical role in aminoglycoside-induced and non-syndromic hearing loss (AINSHL). Previous studies have suggested that mitochondrial secondary variants may modulate the clinical expression of m.1555A>G-induced deafness, but the molecular mechanism has remained largely undetermined. In this study, we investigated the contribution of a deafness-associated tRNAGln 4394C>T mutation to the clinical expression of the m.1555A>G mutation. Interestingly, a three-generation family with both the m.1555A>G and m.4394C>T mutations exhibited a higher penetrance of hearing loss than another family harboring only the m.1555A>G mutation. At the molecular level, the m.4394C>T mutation resides within a very conserved nucleotide of tRNAGln, which forms a new base-pairing (7T-66A) and may affect tRNA structure and function. Using trans-mitochondrial cybrid cells derived from three subjects with both the m.1555A>G and m.4394C>T mutations, three patients with only the m.1555A>G mutation and three control subjects without these primary mutations, we observed that cells with both the m.1555A>G and m.4394C>T mutations exhibited more severely impaired mitochondrial functions than those with only the m.1555A>G mutation. Furthermore, a marked decrease in mitochondrial RNA transcripts and respiratory chain enzymes was observed in cells harboring both the m.1555A>G and m.4394C>T mutations. Thus, our data suggest that the m.4394C>T mutation may play a synergistic role in the m.1555A>G mutation, enhancing mitochondrial dysfunctions and contributing to a high penetrance of hearing loss in families with both mtDNA pathogenic mutations.

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Disease models of Leigh syndrome: From yeast to organoids

Henke,

Prigione,

Schuelke

2024

J of Inher Metab Disea

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Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS‐causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans‐mitochondrial cybrids to more recent model systems such as patient‐derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three‐dimensional organoids. These latter models open the possibility of developing high‐throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.

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Systematic analysis of a mitochondrial disease‐causing ND6 mutation in mitochondrial deficiency

Cited by 6 publications

References 65 publications

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

Mitochondrial tRNAGln 4394C>T Mutation May Contribute to the Clinical Expression of 1555A>G-Induced Deafness

Disease models of Leigh syndrome: From yeast to organoids

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