Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure

Furihata, Takaaki; Takada, Shingo; Kakutani, Naoya; Maékawa, Shohei; Tsuda, Michio; Matsumoto, Junichi; Mizushima, Wataru; Fukushima, Arata; Yokota, Takashi; Enzan, Nobuyuki; Matsushima, Shouji; Handa, Haruka; Fumoto, Yoshizuki; Nio‐Kobayashi, Junko; Iwanaga, Toshihiko; Tanaka, Shinya; Tsutsui, Hiroyuki; Sabe, Hisataka; Kinugawa, Shintaro

doi:10.1038/s42003-021-01675-4

Cited by 24 publications

(35 citation statements)

References 38 publications

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“…As proposed in the model presented in Fig. 7 (based on our results as well as previous publications [27,28]), CISD2 may have specific (e.g., protection of ER and calcium homeostasis) or CISD1 ‐shared (e.g., protection of mitochondria and iron homeostasis) functions during aging.…”

Section: Discussionsupporting

confidence: 78%

The [2Fe‐2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes

et al. 2022

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Considered a key aging gene, CISD2, encoding CDGSH iron-sulfur domaincontaining protein 2, plays a central role in regulating calcium homeostasis, preventing mitochondrial dysfunction, and the activation of autophagy and apoptosis in different cells. Here, we show that cardiomyocytes from CISD2null mice accumulate high levels of iron and contain high levels of transferrin receptor and ferritin. Using proteomics and transmission electron microscopy, we further show that the lack of CISD2 induces several features of the aging process in young mice, but other features are not induced. Taken together, our findings suggest that CISD2 protects cardiomyocytes from overaccumulation of iron, which is common in aging hearts and can contribute to the pathogenesis of heart failure.

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Section: Discussionsupporting

confidence: 78%

The [2Fe‐2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes

et al. 2022

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“…MitoNEET, the iron-sulfur-cluster-containing redox sensor of the mitochondrial outer membrane discovered in the early 2000s, was found to be important for the maintenance of mitochondrial integrity [ 110 ] as it regulates free iron levels, thus preventing the accumulation of iron inside the mitochondrial matrix [ 111 ]. In addition, mitoNEET was shown to regulate the gating of the voltage-dependent anion channel (VDAC, also known as porin) [ 112 ].…”

Section: Contribution Of Mitochondrially Produced Ros To Age-related Changes In Signaling Pathwaysmentioning

confidence: 99%

Oxidative Stress and Energy Metabolism in the Brain: Midlife as a Turning Point

et al. 2021

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Neural tissue is one of the main oxygen consumers in the mammalian body, and a plentitude of metabolic as well as signaling processes within the brain is accompanied by the generation of reactive oxygen (ROS) and nitrogen (RNS) species. Besides the important signaling roles, both ROS and RNS can damage/modify the self-derived cellular components thus promoting neuroinflammation and oxidative stress. While previously, the latter processes were thought to progress linearly with age, newer data point to midlife as a critical turning point. Here, we describe (i) the main pathways leading to ROS/RNS generation within the brain, (ii) the main defense systems for their neutralization and (iii) summarize the recent literature about considerable changes in the energy/ROS homeostasis as well as activation state of the brain’s immune system at midlife. Finally, we discuss the role of calorie restriction as a readily available and cost-efficient antiaging and antioxidant lifestyle intervention.

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“…The studies described above suggest a tight association between NAF-1 protein level and/or function and the protection of cells from overaccumulation of iron and ROS in their mitochondria (a form of ferroptosis, as was shown for cells with reduced expression of mitoNEET, a different member of the NEET protein family; [25,26]). Based on this potential relationship, we hypothesized that treatments that can reduce the levels of iron and ROS in the mitochondria of WFS-T2 patients could ameliorate some of the cell dysfunctions (biochemical and physiological) associated with NAF-1 deficiency in these patients.…”

Section: Introductionmentioning

confidence: 80%

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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Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure

Cited by 24 publications

References 38 publications

The [2Fe‐2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes

The [2Fe‐2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes

Oxidative Stress and Energy Metabolism in the Brain: Midlife as a Turning Point

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

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