Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis

Uzhachenko, Roman V.; Boyd, Kelli L.; Olivares–Villagómez, Danyvid; Zhu, Yueming; Goodwin, J. Shawn; Rana, Tanu; Shanker, Anil; Tan, Winston; Bondar, Tanya; Medzhitov, Ruslan; Ivanova, Alla V.

doi:10.18632/aging.101213

Cited by 23 publications

(47 citation statements)

References 113 publications

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“…Aging is complex set of genetic [40,41], epigenetic [42–46], immunological [47–51], and metabolic [52–58] rearrangements, involving several cellular signalling pathways [59–63] able to regulate metabolism, ROS formation [64–71] and DNA Damage Response (DDR) [72–74] in all organs [75–77]. Therefore, the identification of novel pathways involving p53-mediated responses [78,79] is of crucial interest.…”

Section: Discussionmentioning

confidence: 99%

ZNF185 is a p53 target gene following DNA damage

Smirnov

Cappello

Lena

et al. 2018

Aging

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The transcription factor p53 is a key player in the tumour suppressive DNA damage response and a growing number of target genes involved in these pathways has been identified. p53 has been shown to be implicated in controlling cell motility and its mutant form enhances metastasis by loss of cell directionality, but the p53 role in this context has not yet being investigated. Here, we report that ZNF185, an actin cytoskeleton-associated protein from LIM-family of Zn-finger proteins, is induced following DNA-damage. ChIP-seq analysis, chromatin crosslinking immune-precipitation experiments and luciferase assays demonstrate that ZNF185 is a bona fide p53 target gene. Upon genotoxic stress, caused by DNA-damaging drug etoposide and UVB irradiation, ZNF185 expression is up-regulated and in etoposide-treated cells, ZNF185 depletion does not affect cell proliferation and apoptosis, but interferes with actin cytoskeleton remodelling and cell polarization. Bioinformatic analysis of different types of epithelial cancers from both TCGA and GTEx databases showed a significant decrease in ZNF185 mRNA level compared to normal tissues. These findings are confirmed by tissue micro-array IHC staining. Our data highlight the involvement of ZNF185 and cytoskeleton changes in p53-mediated cellular response to genotoxic stress and indicate ZNF185 as potential biomarker for epithelial cancer diagnosis.

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Section: Discussionmentioning

confidence: 99%

ZNF185 is a p53 target gene following DNA damage

Smirnov

Cappello

Lena

et al. 2018

Aging

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“…E.g. Fis1 KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, perturbed Ca 2+ dynamics, and decreased lifespan (Uzhachenko et al, 2017). Transmembrane protein 135 (TMEM135) is a protein likely involved in mitochondrial fission and mice with mutated TMEM135 display abnormal mitochondrial dynamics and accelerated aging in the retina as well as pathologies observed in agedependent retinal diseases (Lee et al, 2016b).…”

Section: Drosophila Model Shows Opposite Trend Upregulating Drp1 Expmentioning

confidence: 99%

Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases

Giorgi

Marchi

Simões

et al. 2018

International Review of Cell and Molecular Biology

272

162

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Aging has been linked to several degenerative processes that, through the accumulation of molecular and cellular damage, can progressively lead to cell dysfunction and organ failure. Human aging is linked with a higher risk for individuals to develop cancer, neurodegenerative, cardiovascular, and metabolic disorders. The understanding of the molecular basis of aging and associated diseases has been one major challenge of scientific research over the last decades. Mitochondria, the center of oxidative metabolism and principal site of reactive oxygen species (ROS) production, are crucial both in health and in pathogenesis of many diseases. Redox signaling is important for the modulation of cell functions and several studies indicate a dual role for ROS in cell physiology. In fact, high concentrations of ROS are pathogenic and can cause severe damage to cell and organelle membranes, DNA, and proteins. On the other hand, moderate amounts of ROS are essential for the maintenance of several biological processes, including gene expression. In this review, we provide an update regarding the key roles of ROS-mitochondria cross talk in different fundamental physiological or pathological situations accompanying aging and highlighting that mitochondrial ROS may be a decisive target in clinical practice.

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“…The importance of sufficient mitochondrial Ca 2+ uptake was demonstrated in mice lacking Fus1, a small mitochondrial protein regulating mitochondrial Ca 2+ homeostasis. Loss of Fus1 caused inefficient accumulation of Ca 2+ in mitochondria and decreased respiratory reserve capacity, resulting in the decreased lifespan of mice with knockout of Fus1 [ 74 ]. These partly conflicting results suggest that fine-tuning of mitochondrial Ca 2+ homeostasis during aging is a tightrope walk between meeting mitochondria’s demand for Ca 2+ [ 74 ] and triggering harmful processes like increased ROS production or mPTP opening by Ca 2+ overload [ 74 ].…”

Section: Mitochondrial Changes During Agingmentioning

confidence: 99%

Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction

Madreiter‐Sokolowski

Sokołowski

Waldeck-Weiermair

et al. 2018

Genes

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Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca2+ sequestration, fine-tuning mitochondrial activity appropriately, is a tightrope walk during aging. For instance, the mitochondrial oxidative phosphorylation (OXPHOS) ensures a supply of adenosine triphosphate (ATP), but is also the main source of potentially harmful levels of reactive oxygen species (ROS). Moreover, mitochondrial function is strongly linked to mitochondrial Ca2+ homeostasis and mitochondrial shape, which undergo various alterations during aging. Since mitochondria play such a critical role in an organism’s process of aging, they also offer promising targets for manipulation of senescent cellular functions. Accordingly, interventions delaying the onset of age-associated disorders involve the manipulation of mitochondrial function, including caloric restriction (CR) or exercise, as well as drugs, such as metformin, aspirin, and polyphenols. In this review, we discuss mitochondria’s role in and impact on cellular aging and their potential to serve as a target for therapeutic interventions against age-related cellular dysfunction.

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Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis

Cited by 23 publications

References 113 publications

ZNF185 is a p53 target gene following DNA damage

ZNF185 is a p53 target gene following DNA damage

Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases

Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction

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