Functional and therapeutic potential of mitochondrial SIRT3 deacetylase in disease conditions

Kanwal, Abhinav

doi:10.1080/17512433.2018.1546119

Cited by 18 publications

(12 citation statements)

References 53 publications

(59 reference statements)

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“…An emerging role for SIRT3, a member of the sirtuin family mainly localized in the mitochondria, in cellular aging has been outlined by recent studies (Ansari et al, 2017). Through its NAD-dependent deacetylase activity, SIRT3 regulates the mitochondrial metabolic pathways, including FAO (Kanwal, 2018). Specifically, SIRT3 promotes the influx of substrates into the TCA cycle by promoting the activity of PDH and acyl-CoA dehydrogenase (Kincaid and Bossy-Wetzel, 2013).…”

Section: Metabolic Features Of Endothelial Cellsmentioning

confidence: 99%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

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Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD +-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.

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Section: Metabolic Features Of Endothelial Cellsmentioning

confidence: 99%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

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“…DHF appears to ameliorate these changes. DHF has also been shown to exert neuroprotection independently through its antioxidant properties [102,103], and SIRT3 regulates antioxidant activity [104], so DHF may perhaps exert antioxidant effects in Tg26 mice. Mitochondrial dynamics also play an important role in HAND [105].…”

Section: Discussionmentioning

confidence: 99%

7,8-dihydroxyflavone Improves Neuropathological Changes in the Brain of Tg26 Mice, A Model for HIV-associated Neurocognitive Disorder

Bryant

Andhavarapu

Bever

et al. 2020

Preprint

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Background: The combined antiretroviral therapy (cART) era has significantly increased the lifespan of HIV patients, turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In HIV+ patients, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile.Methods: We investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. We immunohistochemically stained brain tissue sections from vehicle-treated wild type (WT), vehicle-treated Tg26, and DHF (5 mg/kg, i.p)-treated Tg26 mice to examine activation of TrkB and downstream signaling, expression of HIV-1 chemokine co-receptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. A one-way ANOVA with a Bonferroni Comparison post-hoc test was performed to analyze the data sets. Results: In the brain regions of Tg26 mice, we observed astrogliosis, increased CXCR4 and CCR5 expression, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB-Akt-NFkB signaling pathway in mediating these pathological hallmarks.Conclusions: Our study provides an overview of how targeting BDNF-TrkB signaling in the pathophysiology of HAND may be relevant for future therapies, and sheds light on 7,8 Dihydroxyflavone as a potential adjunct therapeutic agent to current antiviral therapy.

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“…So far, many different natural and synthetic compounds have been demonstrated to be effective in the regulation of sirtuins, also in the context of myofibroblast activation and differentiation (Table 2). 10,[114][115][116][169][170][171][172][173] One of the most studied natural compounds modulating sirtuin activity is resveratrol (RSV), a polyphenol extracted by grape skin and seeds. 174 This molecule can attenuate several pathological conditions, including fibrosis, and its use has been suggested for preventing various diseases.…”

Section: Sirtuins As Targets Of Natural and Synthetic Antifibrotic Compoundsmentioning

confidence: 99%

Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

Zullo

Mancini

Schleip

et al. 2021

Wound Repair Regeneration

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Fibrotic diseases are still a serious concern for public health, due to their high prevalence, complex etiology and lack of successful treatments. Fibrosis consists of excessive accumulation of extracellular matrix components. As a result, the structure and function of tissues are impaired, thus potentially leading to organ failure and death in several chronic diseases. Myofibroblasts represent the principal cellular mediators of fibrosis, due to their extracellular matrix producing activity, and originate from different types of precursor cells, such as mesenchymal cells, epithelial cells and fibroblasts. Profibrotic activation of myofibroblasts can be triggered by a variety of mechanisms, including the transforming growth factor-β signalling pathway, which is a major factor driving fibrosis. Interestingly, preclinical and clinical studies showed that fibrotic degeneration can stop and even reverse by using specific antifibrotic treatments. Increasing scientific evidence is being accumulated about the role of sirtuins in modulating the molecular pathways responsible for the onset and development of fibrotic diseases. Sirtuins are NAD +dependent protein deacetylases that play a crucial role in several molecular pathways within the cells, many of which at the crossroad between health and disease. In this context, we will report the current knowledge supporting the role of sirtuins in the balance between healthy and diseased myofibroblast activity. In particular, we will address the signalling pathways and the molecular targets that trigger the differentiation and profibrotic activation of myofibroblasts and can be modulated by sirtuins.

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Functional and therapeutic potential of mitochondrial SIRT3 deacetylase in disease conditions

Cited by 18 publications

References 53 publications

Where Metabolism Meets Senescence: Focus on Endothelial Cells

Where Metabolism Meets Senescence: Focus on Endothelial Cells

7,8-dihydroxyflavone Improves Neuropathological Changes in the Brain of Tg26 Mice, A Model for HIV-associated Neurocognitive Disorder

Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

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