Nuclear-Encoded lncRNA MALAT1 Epigenetically Controls Metabolic Reprogramming in HCC Cells through the Mitophagy Pathway

Zhao, Yijing; Zhou, Lei; Li, Hui; Sun, Tingge; Xue, Wei; Li, Xueli; Meng, Ying; Li, Yan; Liu, Mengmeng; Liu, Shanshan; Kim, Su-Jeong; Xiao, Jialin; Li, Lingyu; Zhang, Songling; Li, Wei; Cohen, Pinchas; Hoffman, Andrew R.; Hu, Ji-Fan; Cui, Jiuwei

doi:10.1016/j.omtn.2020.09.040

Cited by 73 publications

(73 citation statements)

References 64 publications

(78 reference statements)

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“…UPR mt prevents abnormal protein accumulation within the mitochondria via normalization of mitochondrial protein folding and degradation [ 14 ]. Mitophagy selectively removes damaged mitochondria via ubiquitination degradation [ 15 ]. In contrast to UPR mt , mitophagy reduces the mitochondrial population, an alteration that is occasionally associated with shortages in ATP and cell death [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

et al. 2021

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Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. Mitophagy and the mitochondrial unfolded protein response (UPR mt ) are the predominant stress-responsive and protective mechanisms involved in repairing damaged mitochondria. Although mitochondrial homeostasis requires the coordinated actions of mitophagy and UPR mt , their molecular basis and interactive actions are poorly understood in sepsis-induced myocardial injury. Our investigations showed that lipopolysaccharide (LPS)-induced sepsis contributed to cardiac dysfunction and mitochondrial damage. Although both mitophagy and UPR mt were slightly activated by LPS in cardiomyocytes, their endogenous activation failed to prevent sepsis-mediated myocardial injury. However, administration of urolithin A, an inducer of mitophagy, obviously reduced sepsis-mediated cardiac depression by normalizing mitochondrial function. Interestingly, this beneficial action was undetectable in cardiomyocyte-specific FUNDC1 knockout (FUNDC1 CKO ) mice. Notably, supplementation with a mitophagy inducer had no impact on UPR mt , whereas genetic ablation of FUNDC1 significantly upregulated the expression of genes related to UPR mt in LPS-treated hearts. In contrast, enhancement of endogenous UPR mt through oligomycin administration reduced sepsis-mediated mitochondrial injury and myocardial dysfunction; this cardioprotective effect was imperceptible in FUNDC1 CKO mice. Lastly, once UPR mt was inhibited, mitophagy-mediated protection of mitochondria and cardiomyocytes was partly blunted. Taken together, it is plausible that endogenous UPR mt and mitophagy are slightly activated by myocardial stress and they work together to sustain mitochondrial performance and cardiac function. Endogenous UPR mt , a downstream signal of mitophagy, played a compensatory role in maintaining mitochondrial homeostasis in the case of mitophagy inhibition. Although UPR mt activation had no negative impact on mitophagy, UPR mt inhibition compromised the partial cardioprotective actions of mitophagy. This study shows how mitophagy modulates UPR mt to attenuate inflammation-related myocardial injury and suggests the potential application of mitophagy and UPR mt targeting in the treatment of myocardial stress.

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Section: Introductionmentioning

confidence: 99%

Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

et al. 2021

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“…Just recently, Zhao and collaborators provided the first evidence that long non-coding RNA (lncRNA) MALAT1 controls metabolic reprogramming in hepatocytes and its downregulation increased the number of swollen mitochondria along with dampened OXPHOS, ATP production and mtDNA copy number. Additionally, MALAT1-deficient cells affected mitophagy by reducing PINK1, SQSTM1/p62, NDP52, BNIP3 and LC3 expression thereby supporting its oncogenic role as lncRNA in HCC onset [191].…”

Section: Metabolic and Epigenetic Dysregulation Of Mitochondrial Metamentioning

confidence: 86%

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

Longo¹,

Paolini²,

Meroni³

et al. 2021

Preprint

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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles which may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlighted that mitochondrial dysfunction due to loss of mitochondrial flexibility, may arise before overt NAFLD and since the early stages of liver injury. Mitochondrial failure not only promotes hepatocellular damage, but also release signals (mito-DAMPs) which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by remodeling of glucidic-lipidic metabolism combined to reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research purposes and for development of potential preventive or curative strategies.

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“…The mitochondria of HCC cells contain a large amount of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MLAT1). MALAT1 knockdown induced alterations in the CpG methylation of mtDNA, and in mitochondrial transcriptomes, at the same time, HCC cells have changes in mitochondrial structure, low oxidative phosphorylation (oxphos), and decreased ATP production [50].…”

Section: Noncoding Rna Is Involved In Regulationmentioning

confidence: 97%

Mechanism, Clinical Significance, and Treatment Strategy of Warburg Effect in Hepatocellular Carcinoma

Chen

Liu

et al. 2021

Journal of Nanomaterials

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Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and the third leading cause of cancer death worldwide. The incidence of HCC accounts for more than 90% of primary HCC. Like most solid malignancies, the occurrence and development of HCC are closely related to the Warburg effect. The Warburg effect of HCC is mainly manifested as increased glucose uptake by HCC cells, increased glycolysis, restricted mitochondrial oxidative phosphorylation, increased pentose phosphate pathway in HCC cells, and increased glutamine decomposition. As the contribution of glycolysis to the total ATP of tumor cells generally does not exceed 50% to 60%, oxidative phosphorylation (OXPHOS) still makes a considerable contribution to the ATP of tumor cells. In some cases, there will be an anti-Warburg effect. HCC Warburg effect is closely related to HCC cell proliferation, apoptosis, immune escape, migration and invasion, chemotherapy resistance, and treatment failure. The mechanism of the Warburg effect in HCC is complex, involving the expression of stimulating the key glycolysis enzymes by hypoxia-inducible factor-1(HIF-1), the activation of oncogenes and the inactivation of tumor suppressor genes, the continuous activation of related signaling pathways, the participation of noncoding RNA, and the rate of metabolism gene mutation of enzyme. This article synthetically discusses the characteristics of glucose metabolism in HCC cells, the mechanism of Warburg effect, clinical significance, and corresponding treatment strategies and provides new perspectives for the prevention and treatment of HCC.

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Nuclear-Encoded lncRNA MALAT1 Epigenetically Controls Metabolic Reprogramming in HCC Cells through the Mitophagy Pathway

Cited by 73 publications

References 64 publications

Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

Mechanism, Clinical Significance, and Treatment Strategy of Warburg Effect in Hepatocellular Carcinoma

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