Spermidine, an autophagy inducer, as a therapeutic strategy in neurological disorders

Ghosh, Indrani; Sankhe, Runali; Mudgal, Jayesh; Arora, Devinder; Nampoothiri, Madhavan

doi:10.1016/j.npep.2020.102083

Cited by 45 publications

(30 citation statements)

References 132 publications

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“…For instance, the effect of cardiovascular-protection and anti-aging of both Spm and Spd were performed through inducing autophagy, reducing age-associated oxidative stress, and inhibiting inflammation. The most frequently reported is that the beneficial effects of Spd are causally connected to the capacity of Spd to induce cytoprotective autophagy/mitophagy by modulating the expressions of Atg genes, promoting the acetylation of Atg genes by inhibiting EP300, and suppressing histone acetylation ( Madeo et al, 2018 ; Ghosh et al, 2020 ). Spd inhibited aging-associated pathologies, and pro-inflammatory status is closely associated with autophagy inducing, which would lead to improvement of mitochondrial metabolism and respiration as well as proteostasis ( Singh et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Dynamic Mitochondrial Proteome Under Polyamines Treatment in Cardiac Aging

Zhang

Liu

et al. 2022

Front. Cell Dev. Biol.

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Age-related alteration of mitochondria causes impaired cardiac function, along with cellular and molecular changes. Polyamines can extend the life span in mice. However, whether polyamines can affect the dynamic mitochondrial proteome, thereby preventing age-related changes in cardiac function and cardiac aging, remains unclear. In this study, we found that spermine (Spm) and spermidine (Spd) injection for 6 weeks could prevent 24-month-old rats heart dysfunction, improve mitochondrial function, and downregulate apoptosis. Using iTRAQ tools, we identify 75 mitochondrial proteins of statistically significant alteration in aging hearts, which mainly participate in important mitochondrial physiological activity, such as metabolism, translation, transport, apoptosis, and oxidative phosphorylation. Moreover, four proteins of differential expression, pyruvate dehydrogenase kinase (PDK4), trifunctional enzyme subunit alpha (HADHA), nicotinamide nucleotide transhydrogenase (NNT), and Annexin6, which were significantly associated with heart aging, were validated by Western blotting. In vitro, we further demonstrated polyamines could retard cardiomyocytes aging through downregulating the expression of PDK4 and thereby inhibiting cell apoptosis. In summary, the distinct mitochondrial proteins identified in this study suggested some candidates involved in the anti-aging of the heart after polyamines treatment, and PDK4 may provide molecular clues for polyamines to inhibit apoptosis and thus retard aging-induced cardiac dysfunction.

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Section: Discussionmentioning

confidence: 99%

Dynamic Mitochondrial Proteome Under Polyamines Treatment in Cardiac Aging

Zhang

Liu

et al. 2022

Front. Cell Dev. Biol.

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“…Polyamines can get synthesized downstream of L-ornithine by the ODC1 and further reversibly processed from putrescine to spermidine and spermine. The roles of polyamines in cells are broad and vary from cell proliferation to gene expression, ion channel regulation, and protection from oxidative damage to autophagy and regulatory aspects in immune cells [36][37][38][39]. Other studies using carbon tetrachloride (CCl 4 ) or ethanol for inducing liver injury demonstrated a protective effect of polyamines as well as a positive effect on hepatocyte proliferation [40,41].…”

Section: Discussionmentioning

confidence: 99%

Physical Interaction between Embryonic Stem Cell-Expressed Ras (ERas) and Arginase-1 in Quiescent Hepatic Stellate Cells

Pudewell

Lissy

Nakhaeizadeh

et al. 2022

Cells

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Embryonic stem cell-expressed Ras (ERas) is an atypical constitutively active member of the Ras family and controls distinct signaling pathways, which are critical, for instance, for the maintenance of quiescent hepatic stellate cells (HSCs). Unlike classical Ras paralogs, ERas has a unique N-terminal extension (Nex) with as yet unknown function. In this study, we employed affinity pull-down and quantitative liquid chromatography-tandem mass spectrometry (LC–MS/MS) analyses and identified 76 novel binding proteins for human and rat ERas Nex peptides, localized in different subcellular compartments and involved in various cellular processes. One of the identified Nex-binding proteins is the nonmitochondrial, cytosolic arginase 1 (ARG1), a key enzyme of the urea cycle and involved in the de novo synthesis of polyamines, such as spermidine and spermine. Here, we show, for the first time, a high-affinity interaction between ERas Nex and purified ARG1 as well as their subcellular colocalization. The inhibition of ARG1 activity strikingly accelerates the activation of HSCs ex vivo, suggesting a central role of ARG1 activity in the maintenance of HSC quiescence.

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“…SPD also exerts cardiac and neuronal protection through activation of mitophagy and clearance of dysfunctional mitochondria [14,40]. Having healthy mitochondria is crucial for liver homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Spermidine Supplementation Protects the Liver Endothelium from Liver Damage in Mice

et al. 2021

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Chronic liver diseases are multifactorial and the need to develop effective therapies is high. Recent studies have shown the potential of ameliorating liver disease progression through protection of the liver endothelium. Polyamine spermidine (SPD) is a caloric restriction mimetic with autophagy-enhancing properties capable of prolonging lifespan and with a proven beneficial effect in cardiovascular disease in mice and humans. We evaluated the use of dietary supplementation with SPD in two models of liver disease (CCl4 and CDAAH diet). We analyzed the effect of SPD on endothelial dysfunction in vitro and in vivo. C57BL/6J mice were supplemented with SPD in the drinking water prior and concomitantly with CCl4 and CDAAH treatments. Endothelial autophagy deficient (Atg7endo) mice were also evaluated. Liver tissue was used to evaluate the impact of SPD prophylaxis on liver damage, endothelial dysfunction, oxidative stress, mitochondrial status, inflammation and liver fibrosis. SPD improved the endothelial response to oxidative injury in vitro and improved the liver endothelial phenotype and protected against liver injury in vivo. SPD reduced the overall liver oxidative stress and improved mitochondrial fitness. The absence of benefits in the Atg7endo mice suggests an autophagy-dependent effect of SPD. This study suggests SPD diet supplementation in early phases of disease protects the liver endothelium from oxidative stress and may be an attractive approach to modify the chronic liver disease course and halt fibrosis progression.

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Spermidine, an autophagy inducer, as a therapeutic strategy in neurological disorders

Cited by 45 publications

References 132 publications

Dynamic Mitochondrial Proteome Under Polyamines Treatment in Cardiac Aging

Dynamic Mitochondrial Proteome Under Polyamines Treatment in Cardiac Aging

Physical Interaction between Embryonic Stem Cell-Expressed Ras (ERas) and Arginase-1 in Quiescent Hepatic Stellate Cells

Spermidine Supplementation Protects the Liver Endothelium from Liver Damage in Mice

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