Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission

Ma, Dong; Zheng, Bin; Liu, Heliang; Zhao, Yongbo; Liu, Xiao; Zhang, Xinhua; Li, Qiang; Shi, Wanying; Suzuki, Toru; Wen, Jin‐Kun

doi:10.1371/journal.pbio.3000808

Cited by 55 publications

(43 citation statements)

References 68 publications

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“…55 Recently, a study showed that negative regulation of eIF5A induced by Klf5 knockdown, resulted in mitochondrial fission, demonstrating that eIF5a can act in the regulation of mitochondrial dynamics. 56 Here, we described for the first time the eIF5A isoform A functions regarding mitochondrial metabolism. Initially, cell activity was measured by MTT conversion in formazan through the action of NAD(P)H-dependent oxidoreductase enzymes.…”

Section: Discussionmentioning

confidence: 93%

“…This effect was reported as a consequence of the negative regulation of mitochondrial complexes induced by eIF5A hypusination inhibition 55 . Recently, a study showed that negative regulation of eIF5A induced by Klf5 knockdown, resulted in mitochondrial fission, demonstrating that eIF5a can act in the regulation of mitochondrial dynamics 56 …”

Section: Discussionmentioning

confidence: 94%

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Alternative human eIF5A protein isoform plays a critical role in mitochondria

Pereira

Tamborlin

Lima

et al. 2021

J of Cellular Biochemistry

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The eukaryotic translation initiation factor 5A (eIF5A) is the only known protein containing the amino acid residue hypusine, essential for its activity. Hypusine residue is produced by a posttranslational modification involving deoxyhypusine synthetase and deoxyhypusine hydroxylase. Herein, we aimed to describe the role of the alternative human isoform A on mitochondrial processes. Isoform A depletion modulates oxidative metabolism in association with the downregulation of mitochondrial biogenesis-related genes. Through positive feedback, it increases cell respiration leading to highly reactive oxygen species production, which impacts mitochondrial bioenergetics. These metabolic changes compromise mitochondrial morphology, increasing its electron density and fission, observed by transmission electron microscopy. This set of changes leads the cells to apoptosis, evidenced by increased DNA fragmentation and proapoptotic BAK protein content increase. Thus, we show that the alternative eIF5A isoform A is crucial for energy metabolism controlled by mitochondria and cellular survival.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Alternative human eIF5A protein isoform plays a critical role in mitochondria

Pereira

Tamborlin

Lima

et al. 2021

J of Cellular Biochemistry

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“…When overexpressed, this longer isoform co-purifies with mitochondria [ 26 ]. Secondly, there is evidence for the role of eIF5A in preserving mitochondrial morphology, distribution and integrity, obtained in Schizosaccharomyces pombe and mammals [ 27 , 28 ]. Thirdly, the connection between eIF5A and mitochondria-mediated apoptosis has been described, where eIF5A overexpression in human cells increased reactive oxygen species (ROS) and yielded loss of the mitochondrial transmembrane potential, and the release of cytochrome-c and caspase activation [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Yeast Translation Elongation Factor eIF5A Expression Is Regulated by Nutrient Availability through Different Signalling Pathways

Barba‐Aliaga

Villarroel-Vicente

Stanciu

et al. 2020

IJMS

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Translation elongation factor eIF5A binds to ribosomes to promote peptide bonds between problematic amino acids for the reaction like prolines. eIF5A is highly conserved and essential in eukaryotes, which usually contain two similar but differentially expressed paralogue genes. The human eIF5A-1 isoform is abundant and implicated in some cancer types; the eIF5A-2 isoform is absent in most cells but becomes overexpressed in many metastatic cancers. Several reports have connected eIF5A and mitochondria because it co-purifies with the organelle or its inhibition reduces respiration and mitochondrial enzyme levels. However, the mechanisms of eIF5A mitochondrial function, and whether eIF5A expression is regulated by the mitochondrial metabolism, are unknown. We analysed the expression of yeast eIF5A isoforms Tif51A and Tif51B under several metabolic conditions and in mutants. The depletion of Tif51A, but not Tif51B, compromised yeast growth under respiration and reduced oxygen consumption. Tif51A expression followed dual positive regulation: by high glucose through TORC1 signalling, like other translation factors, to promote growth and by low glucose or non-fermentative carbon sources through Snf1 and heme-dependent transcription factor Hap1 to promote respiration. Upon iron depletion, Tif51A was down-regulated and Tif51B up-regulated. Both were Hap1-dependent. Our results demonstrate eIF5A expression regulation by cellular metabolic status.

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“…In the same study the authors reported that over‐expression of eIF5A1 induced activation of caspase-3, -8, and -9 together with a loss of the mitochondrial transmembrane potential, release of cytochrome c , and translocation of Bax. Analysing the mitochondrial dynamics linked to cellular senescence Ma et al [ 86 ] reported that the Kruppel like factor 5 (KLF5 an essential transcriptional factor of cardiovascular remodeling, that mediates the link between mitochondrial dynamics and vascular smooth muscle cell senescence) knockdown enhanced, while KLF5 over-expression suppressed mitochondrial fission. Mechanistically, KLF5 activates eIF5A transcription through binding to its promoter, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1).…”

Section: Apoptosis and Mitochondriamentioning

confidence: 99%

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

et al. 2021

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Since the demonstration of its involvement in cell proliferation, the eukaryotic initiation factor 5A (eIF5A) has been studied principally in relation to the development and progression of cancers in which the isoform A2 is mainly expressed. However, an increasing number of studies report that the isoform A1, which is ubiquitously expressed in normal cells, exhibits novel molecular features that reveal its new relationships between cellular functions and organ homeostasis. At a first glance, eIF5A can be regarded, among other things, as a factor implicated in the initiation of translation. Nevertheless, at least three specificities: (1) its extreme conservation between species, including plants, throughout evolution, (2) its very special and unique post-translational modification through the activating-hypusination process, and finally (3) its close relationship with the polyamine pathway, suggest that the role of eIF5A in living beings remains to be uncovered. In fact, and beyond its involvement in facilitating the translation of proteins containing polyproline residues, eIF5A is implicated in various physiological processes including ischemic tolerance, metabolic adaptation, aging, development, and immune cell differentiation. These newly discovered physiological properties open up huge opportunities in the clinic for pathologies such as, for example, the ones in which the oxygen supply is disrupted. In this latter case, organ transplantation, myocardial infarction or stroke are concerned, and the current literature defines eIF5A as a new drug target with a high level of potential benefit for patients with these diseases or injuries. Moreover, the recent use of genomic and transcriptomic association along with metadata studies also revealed the implication of eIF5A in genetic diseases. Thus, this review provides an overview of eIF5A from its molecular mechanism of action to its physiological roles and the clinical possibilities that have been recently reported in the literature.

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Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission

Cited by 55 publications

References 68 publications

Alternative human eIF5A protein isoform plays a critical role in mitochondria

Alternative human eIF5A protein isoform plays a critical role in mitochondria

Yeast Translation Elongation Factor eIF5A Expression Is Regulated by Nutrient Availability through Different Signalling Pathways

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

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