Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output

Zhao, Qiyi; Liu, Jiayu; Deng, Hong; Ma, Xiaoqiang; Liao, Jian-You; Liang, Huixin; Hu, Jingxiong; Li, Jiaqian; Guo, Zhiyong; Cai, Junchao; Xu, Xiaoding; Gao, Zhiliang; Su, Shicheng

doi:10.1016/j.cell.2020.08.009

Cited by 259 publications

(235 citation statements)

References 96 publications

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“…Mitochondrial genome-encoded circRNAs (mt-circRNAs) account for a considerable fraction of RNA components in the mitochondria, however, the biological function of mt-circRNAs is still not understood. Based on existing studies on the mt-circRNAs, steatohepatitis-associated circRNA ATP5B regulator (SCAR) plays a pivotal role in mROS metabolism and fibroblast activation, and mc-COX2 modulates mitochondrial function and regulates chronic lymphocytic leukemia cell proliferation and apoptosis 76 , 77 . Unlike the traditional circRNAs, the mt-circRNAs may work via new mechanisms instead of acting as the competing endogenous RNA.…”

Section: Discussionmentioning

confidence: 99%

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia

Li¹,

Wang²,

Li³

et al. 2021

Theranostics

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Background: Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. Methods: A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O 2 environment. Results: MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. Conclusions: This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia

Li¹,

Wang²,

Li³

et al. 2021

Theranostics

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“…For example, recent studies have highlighted that the presence of a particular circRNA from SLC45A4 is essential to keep neural cells in a progenitor state in the mammalian brain ( Suenkel et al, 2020 ). Recently, the regulatory functions of two circRNAs produced respectively from a mitochondrial gene ( Zhao et al, 2020 ) and from an intron ( Das et al, 2020 ; Stoll et al, 2020 ) were characterized. These studies have also underlined the need to work on the conservation of circRNAs, and beyond exonic circRNAs.…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of the Circular Transcriptome in Muscle, Liver, and Testis in Three Livestock Species

et al. 2021

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Circular RNAs have been observed in a large number of species and tissues and are now recognized as a clear component of the transcriptome. Our study takes advantage of functional datasets produced within the FAANG consortium to investigate the pervasiveness of circular RNA transcription in farm animals. We describe here the circular transcriptional landscape in pig, sheep and bovine testicular, muscular and liver tissues using total 66 RNA-seq datasets. After an exhaustive detection of circular RNAs, we propose an annotation of exonic, intronic and sub-exonic circRNAs and comparative analyses of circRNA content to evaluate the variability between individuals, tissues and species. Despite technical bias due to the various origins of the datasets, we were able to characterize some features (i) (ruminant) liver contains more exonic circRNAs than muscle (ii) in testis, the number of exonic circRNAs seems associated with the sexual maturity of the animal. (iii) a particular class of circRNAs, sub-exonic circRNAs, are produced by a large variety of multi-exonic genes (protein-coding genes, long non-coding RNAs and pseudogenes) and mono-exonic genes (protein-coding genes from mitochondrial genome and small non-coding genes). Moreover, for multi-exonic genes there seems to be a relationship between the sub-exonic circRNAs transcription level and the linear transcription level. Finally, sub-exonic circRNAs produced by mono-exonic genes (mitochondrial protein-coding genes, ribozyme, and sno) exhibit a particular behavior. Caution has to be taken regarding the interpretation of the unannotated circRNA proportion in a given tissue/species: clusters of circRNAs without annotation were characterized in genomic regions with annotation and/or assembly problems of the respective animal genomes. This study highlights the importance of improving genome annotation to better consider candidate circRNAs and to better understand the circular transcriptome. Furthermore, it emphasizes the need for considering the relative “weight” of circRNAs/parent genes for comparative analyses of several circular transcriptomes. Although there are points of agreement in the circular transcriptome of the same tissue in two species, it will be not possible to do without the characterization of it in both species.

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“…Overexpression of SCAR in NASH fibroblasts blocked mPTP opening, inhibiting mitochondrial ROS output and subsequent fibroblast activation. In mice fed a high-fat diet, specific delivery of SCAR to liver fibroblasts using mitochondria-targeting nanoparticles alleviates cirrhosis and insulin resistance accompanied with NASH [ 252 ].…”

Section: Higher Organization Of the Mitochondrial Genomementioning

confidence: 99%

Mitochondrial nucleoid in cardiac homeostasis: bidirectional signaling of mitochondria and nucleus in cardiac diseases

et al. 2021

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Metabolic function and energy production in eukaryotic cells are regulated by mitochondria, which have been recognized as the intracellular ‘powerhouses’ of eukaryotic cells for their regulation of cellular homeostasis. Mitochondrial function is important not only in normal developmental and physiological processes, but also in a variety of human pathologies, including cardiac diseases. An emerging topic in the field of cardiovascular medicine is the implication of mitochondrial nucleoid for metabolic reprogramming. This review describes the linear/3D architecture of the mitochondrial nucleoid (e.g., highly organized protein-DNA structure of nucleoid) and how it is regulated by a variety of factors, such as noncoding RNA and its associated R-loop, for metabolic reprogramming in cardiac diseases. In addition, we highlight many of the presently unsolved questions regarding cardiac metabolism in terms of bidirectional signaling of mitochondrial nucleoid and 3D chromatin structure in the nucleus. In particular, we explore novel techniques to dissect the 3D structure of mitochondrial nucleoid and propose new insights into the mitochondrial retrograde signaling, and how it regulates the nuclear (3D) chromatin structures in mitochondrial diseases.

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Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output

Cited by 259 publications

References 96 publications

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia

Comparative Analysis of the Circular Transcriptome in Muscle, Liver, and Testis in Three Livestock Species

Mitochondrial nucleoid in cardiac homeostasis: bidirectional signaling of mitochondria and nucleus in cardiac diseases

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