CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma

Shen, Zhao Qing; Chen, Yi Fan; Chen, Jim Ray; Jou, Yuh–Shan; Wu, Po‐Kuei; Kao, Chiang; Wang, Chih-Hao; Huang, Yi; Chen, Chian Feng; Huang, Ting; Shyu, Yu-Chiau; Tsai, Shih Feng; Kao, Lung‐Sen; Tsai, Ting Fen

doi:10.1016/j.celrep.2017.10.099

Cited by 60 publications

(51 citation statements)

References 36 publications

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“…There are two Dosmit homologs in mammals: Cisd1 and Cisd2 51,52 . These two proteins show different subcellular localization patterns and may have distinct functions, since Cisd2 has a longer N-terminal domain and is located mainly in the ER 63 , while Cisd1 has a shorter N-terminal domain and is located mainly on mitochondria 51 ( Supplementary Fig. 16b).…”

Section: Discussionmentioning

confidence: 99%

Vesicular transport mediates the uptake of cytoplasmic proteins into mitochondria in Drosophila melanogaster

et al. 2020

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Mitochondrial aging, which results in mitochondrial dysfunction, is strongly linked to many age-related diseases. Aging is associated with mitochondrial enlargement and transport of cytosolic proteins into mitochondria. The underlying homeostatic mechanisms that regulate mitochondrial morphology and function, and their breakdown during aging, remain unclear. Here, we identify a mitochondrial protein trafficking pathway in Drosophila melanogaster involving the mitochondria-associated protein Dosmit. Dosmit induces mitochondrial enlargement and the formation of double-membraned vesicles containing cytosolic protein within mitochondria. The rate of vesicle formation increases with age. Vesicles originate from the outer mitochondrial membrane as observed by tracking Tom20 localization, and the process is mediated by the mitochondria-associated Rab32 protein. Dosmit expression level is closely linked to the rate of ubiquitinated protein aggregation, which are themselves associated with age-related diseases. The mitochondrial protein trafficking route mediated by Dosmit offers a promising target for future age-related mitochondrial disease therapies.

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Section: Discussionmentioning

confidence: 99%

Vesicular transport mediates the uptake of cytoplasmic proteins into mitochondria in Drosophila melanogaster

et al. 2020

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“…Secondly, UPR causes upregulation of the tribbles homolog 3 (TRB3), which inhibits signaling via the insulin receptor axis ( 133 , 134 ). In addition to insulin resistance, elegant studies using a genetic mouse model of impaired ER calcium reuptake by genetic ablation of the SERCA activator Cisd2 have implicated reduced ER calcium levels and resulting ER stress in the development and progression of NAFLD ( 135 ).…”

Section: Calcium Signaling In Chronic Liver Injurymentioning

confidence: 99%

Calcium Signaling in Liver Injury and Regeneration

et al. 2018

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The liver fulfills central roles in metabolic control and detoxification and, as such, is continuously exposed to a plethora of insults. Importantly, the liver has a unique ability to regenerate and can completely recoup from most acute, non-iterative insults. However, multiple conditions, including viral hepatitis, non-alcoholic fatty liver disease (NAFLD), long-term alcohol abuse and chronic use of certain medications, can cause persistent injury in which the regenerative capacity eventually becomes dysfunctional, resulting in hepatic scaring and cirrhosis. Calcium is a versatile secondary messenger that regulates multiple hepatic functions, including lipid and carbohydrate metabolism, as well as bile secretion and choleresis. Accordingly, dysregulation of calcium signaling is a hallmark of both acute and chronic liver diseases. In addition, recent research implicates calcium transients as essential components of liver regeneration. In this review, we provide a comprehensive overview of the role of calcium signaling in liver health and disease and discuss the importance of calcium in the orchestration of the ensuing regenerative response. Furthermore, we highlight similarities and differences in spatiotemporal calcium regulation between liver insults of different etiologies. Finally, we discuss intracellular calcium control as an emerging therapeutic target for liver injury and summarize recent clinical findings of calcium modulation for the treatment of ischemic-reperfusion injury, cholestasis and NAFLD.

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“…Although both diagnostic and therapeutic strategies for HCC have improved over the past decades, the 5-year survival rate only is around 10%, and HCC continues to be a global health issue, especially in Asian countries [ 3 , 4 ]. Emerging evidence suggested that nonalcoholic fatty liver disease (NAFLD), a common disorder in obese people, is a significant risk factor for HCC [ 5 , 6 ]. Given the global prevalence of obesity, there is the looming threat of a rapidly rising occurrence of NAFLD-related HCC.…”

Section: Introductionmentioning

confidence: 99%

Exosomes released by hepatocarcinoma cells endow adipocytes with tumor-promoting properties

et al. 2018

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BackgroundThe initiation and progression of hepatocellular carcinoma (HCC) are largely dependent on its local microenvironment. Adipocytes are an important component of hepatic microenvironment in nonalcoholic fatty liver disease (NAFLD), which is a significant risk factor for HCC. Given the global prevalence of NAFLD, a better understanding of the interplay between HCC cells and adipocytes is urgently needed. Exosomes, released by malignant cells, represent a novel way of cell-cell interaction and have been shown to play an important role in cancer cell communication with their microenvironment. Here, we explore the role of HCC-derived exosomes in the cellular and molecular conversion of adipocytes into tumor-promoting cells.MethodsExosomes were isolated from HCC cell line HepG2 and added to adipocytes. Transcriptomic alterations of exosome-stimulated adipocytes were analyzed using gene expression profiling, and secretion of inflammation-associated cytokines was detected by RT-PCR and ELISA. In vivo mouse xenograft model was used to evaluate the growth-promoting and angiogenesis-enhancing effects of exosome-treated adipocytes. Protein content of tumor exosomes was analyzed by mass spectrometry. Activated phospho-kinases involved in exosome-treated adipocytes were detected by phospho-kinase antibody array and Western blot.ResultsOur results demonstrated that HCC cell HepG2-derived exosomes could be actively internalized by adipocytes and caused significant transcriptomic alterations and in particular induced an inflammatory phenotype in adipocytes. The tumor exosome-treated adipocytes, named exo-adipocytes, promoted tumor growth, enhanced angiogenesis, and recruited more macrophages in mouse xenograft model. In vitro, conditioned medium from exo-adipocytes promoted HepG2 cell migration and increased tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, we found HepG2 exosomes activated several phopho-kinases and NF-κB signaling pathway in exo-adipocytes. Additionally, a total of 1428 proteins were identified in HepG2 exosomes by mass spectrometry.ConclusionsOur results provide new insights into the concept that tumor cell-derived exosomes can educate surrounding adipocytes to create a favorable microenvironment for tumor progression.

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CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma

Cited by 60 publications

References 36 publications

Vesicular transport mediates the uptake of cytoplasmic proteins into mitochondria in Drosophila melanogaster

Vesicular transport mediates the uptake of cytoplasmic proteins into mitochondria in Drosophila melanogaster

Calcium Signaling in Liver Injury and Regeneration

Exosomes released by hepatocarcinoma cells endow adipocytes with tumor-promoting properties

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