CISD2 maintains cellular homeostasis

Shen, Zhao Qing; Huang, Yi; Teng, Yuan; Wang, Tai Wen; Kao, Chiang; Yeh, Chi-Hsiao; Tsai, Ting Fen

doi:10.1016/j.bbamcr.2021.118954

Cited by 55 publications

(51 citation statements)

References 119 publications

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“…Aside from NAF-1(−) induced changes in mitochondria-ER MAM integrity (Figures 2 and 3), the multiple changes observed in INS-1E cells upon NAF-1 suppression recapitulate what we and others have observed in previous studies with non-endocrine cells in culture and with animal models of WFS-T2 (i.e., knockouts of NAF-1) [15,[60][61][62]. The novel finding of this work is therefore the establishment of a causative association between NAF-1 repression that leads to a mitochondrial labile iron rise and an increased mROS formation that triggers ferroptosis, and the impairment of β-cell insulin secretion.…”

Section: Discussionsupporting

confidence: 86%

A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells

et al. 2021

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Decreased insulin secretion, associated with pancreatic β-cell failure, plays a critical role in many human diseases including diabetes, obesity, and cancer. While numerous studies linked β-cell failure with enhanced levels of reactive oxygen species (ROS), the development of diabetes associated with hereditary conditions that result in iron overload, e.g., hemochromatosis, Friedreich's ataxia, and Wolfram syndrome type 2 (WFS-T2; a mutation in CISD2, encoding the [2Fe-2S] protein NAF-1), underscores an additional link between iron metabolism and β-cell failure. Here, using NAF-1-repressed INS-1E pancreatic cells, we observed that NAF-1 repression inhibited insulin secretion, as well as impaired mitochondrial and ER structure and function. Importantly, we found that a combined treatment with the cell permeant iron chelator deferiprone and the glutathione precursor N-acetyl cysteine promoted the structural repair of mitochondria and ER, decreased mitochondrial labile iron and ROS levels, and restored glucose-stimulated insulin secretion. Additionally, treatment with the ferroptosis inhibitor ferrostatin-1 decreased cellular ROS formation and improved cellular growth of NAF-1 repressed pancreatic cells. Our findings reveal that suppressed expression of NAF-1 is associated with the development of ferroptosis-like features in pancreatic cells, and that reducing the levels of mitochondrial iron and ROS levels could be used as a therapeutic avenue for WFS-T2 patients.

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Section: Discussionsupporting

confidence: 86%

A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells

et al. 2021

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“…In addition, one of our previous studies revealed that Cisd2 regulates calcium homeostasis and the mitochondrial function [ 11 ]. In this study, we carried out quantification of the proteins involved in these biological processes in the liver.…”

Section: Resultsmentioning

confidence: 99%

“…Among these antioxidant enzymes, two of them, namely Glrx and Prdx3, were found to be downregulated in the 26-mo Cisd2TG mice compared to the 26-mo WT mice (Figure 5C). In addition, one of our previous studies revealed that Cisd2 regulates calcium homeostasis and the mitochondrial function [11]. In this study, we carried out quantification of the proteins involved in these biological processes in the liver.…”

Section: Cisd2 Modulates the Redox Status Calcium Homeostasis And Mitochondrial Respirationmentioning

confidence: 98%

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Cisd2 Preserves the Youthful Pattern of the Liver Proteome during Natural Aging of Mice

Huang

Shen

et al. 2021

Biomedicines

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Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provide pathological and molecular evidence to show that Cisd2 protects the liver from age-related dysregulation of lipid metabolism and protein homeostasis. This study makes four major discoveries. Firstly, a persistently high level of Cisd2 protects the liver from age-related fat accumulation. Secondly, proteomics analysis revealed that Cisd2 ameliorates age-related dysregulation of lipid metabolism, including lipid biosynthesis and β-oxidation, in mitochondria and peroxisomes. Thirdly, Cisd2 attenuates aging-associated oxidative modifications of proteins. Finally, Cisd2 regulates intracellular protein homeostasis by maintaining the functionality of molecular chaperones and protein synthesis machinery. Our proteomics findings highlight Cisd2 as a novel molecular target for the development of therapies targeting fatty liver diseases, and these new therapies are likely to help prevent subsequent malignant progression to cirrhosis and hepatocellular carcinoma.

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“…C isd2 is an evolutionally conserved gene that plays an essential role in mediating mammalian lifespan [ 14 ]. The Cisd2 protein is mainly located in the mitochondrial outer membrane, the endoplasmic reticulum (ER), and the mitochondria-associated membranes (MAMs).…”

Section: Introductionmentioning

confidence: 99%

Rejuvenating the Aging Heart by Enhancing the Expression of the Cisd2 Prolongevity Gene

Yeh

Chou

Tsai

2021

IJMS

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Aging is the major risk factor for cardiovascular disease, which is the leading cause of mortality worldwide among aging populations. Cisd2 is a prolongevity gene that mediates lifespan in mammals. Previously, our investigations revealed that a persistently high level of Cisd2 expression in mice is able to prevent age-associated cardiac dysfunction. This study was designed to apply a genetic approach that induces cardiac-specific Cisd2 overexpression (Cisd2 icOE) at a late-life stage, namely a time point immediately preceding the onset of old age, and evaluate the translational potential of this approach. Several discoveries are pinpointed. Firstly, Cisd2 is downregulated in the aging heart. This decrease in Cisd2 leads to cardiac dysfunction and impairs electromechanical performance. Intriguingly, Cisd2 icOE prevents an exacerbation of age-associated electromechanical dysfunction. Secondly, Cisd2 icOE ameliorates cardiac fibrosis and improves the integrity of the intercalated discs, thereby reversing various structural abnormalities. Finally, Cisd2 icOE reverses the transcriptomic profile of the aging heart, changing it from an older-age pattern to a younger pattern. Intriguingly, Cisd2 icOE modulates a number of aging-related pathways, namely the sirtuin signaling, autophagy, and senescence pathways, to bring about rejuvenation of the heart as it enters old age. Our findings highlight Cisd2 as a novel molecular target for developing therapies targeting cardiac aging.

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CISD2 maintains cellular homeostasis

Cited by 55 publications

References 119 publications

A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells

A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells

Cisd2 Preserves the Youthful Pattern of the Liver Proteome during Natural Aging of Mice

Rejuvenating the Aging Heart by Enhancing the Expression of the Cisd2 Prolongevity Gene

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