Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Inhibits Vascular Calcification Through Sirtuin 3-Mediated Reduction of Mitochondrial Oxidative Stress

Feng, Han‐Zhong; Wang, Jinyu; B, Yu; Cong, Xin; Zhang, Weiguang; Li, Li; Liu, Limei; Zhou, Yun; Zhang, Chenglin; Gu, Pei-Liang; Wu, Li‐Ling

doi:10.1089/ars.2018.7620

Cited by 37 publications

(41 citation statements)

References 57 publications

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“…Mitochondrial activity is still essential for the generation of NAD(P)H and FAD to support the Warburg effect [12,13]. Sirtuins regulate the expression of several downstream pro-mitochondrial genes such as uncoupling protein-2 (UCP2), peroxisome proliferatoractivated receptor-γ (PPAR-γ) and PPAR-γ coactivator 1-α (PGC1α) [74,75]. UCP2 is a mitochondrial uncoupling protein, resident in the inner mitochondrial membrane, which dissipates the proton motive force by allowing protons to flow down their concentration gradient back into the mitochondrial matrix.…”

Section: Nnmt Increases Mitochondrial Functionmentioning

confidence: 99%

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Parsons

Facey

2021

Biomolecules

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Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a central role for NNMT in cancer survival, metastasis, and drug resistance. In this review, we discuss the evidence supporting a role for NNMT in the progression of the cancer phenotype and how it achieves this by driving the activity of pro-oncogenic NAD+-consuming enzymes. We also describe how increased NNMT activity supports the Warburg effect and how it promotes oncogenic changes in gene expression. We discuss the regulation of NNMT activity in cancer cells by both post-translational modification of the enzyme and transcription factor binding to the NNMT gene, and describe for the first time three long non-coding RNAs which may play a role in the regulation of NNMT transcription. We complete the review by discussing the development of novel anti-cancer therapeutics which target NNMT and provide insight into how NNMT-based therapies may be best employed clinically.

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Section: Nnmt Increases Mitochondrial Functionmentioning

confidence: 99%

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Parsons

Facey

2021

Biomolecules

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“…At present, 3-TYP is mainly used to study the regulation of SIRT3 on mROS homeostasis and autophagic flux, which is reflected in the study of ischemia-reperfusion injury and some drugs (such as genipin and melatonin; Pi et al, 2015; Zhai et al, 2017; Shumin et al, 2018; Ouyang et al, 2019). 3-TYP has also been used to study the relationship between some upstream factors (including PGC-1α and SIRT1) and SIRT3 (Feng et al, 2019; Liu et al, 2019), as well as the regulation of mitophagy by SIRT3 (Wang et al, 2019). As a new method, SIRT3 inhibitors may play an important role in future research into SIRT3.…”

Section: Future Directionsmentioning

confidence: 99%

SIRT3 Regulation of Mitochondrial Quality Control in Neurodegenerative Diseases

Meng

Yan

Lei

et al. 2019

Front. Aging Neurosci.

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Neurodegenerative diseases are disorders that are characterized by a progressive decline of motor and/or cognitive functions caused by the selective degeneration and loss of neurons within the central nervous system. The most common neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Neurons have high energy demands, and dysregulation of mitochondrial quality and function is an important cause of neuronal degeneration. Mitochondrial quality control plays an important role in maintaining mitochondrial integrity and ensuring normal mitochondrial function; thus, defects in mitochondrial quality control are also significant causes of neurodegenerative diseases. The mitochondrial deacetylase SIRT3 has been found to have a large effect on mitochondrial function. Recent studies have also shown that SIRT3 has a role in mitochondrial quality control, including in the refolding or degradation of misfolded/unfolded proteins, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis, all of which are affected in neurodegenerative diseases.

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“…We summarized available reports focusing on the upstream regulatory molecules of SOD2 in VSMCs in (Figure 1). Using cultured VSMCs and calcified aortas from CKD rats, Feng et al disclosed that SIRT3 upregulated Sod2 expressions, attenuated mtROS, and retarded VSMC calcification, while SIRT3 inhibition exhibited the reverse phenotypes [56]. They further discovered that PGC-1α was an important endogenous activator of SIRT3 and could effectively defend against vascular calcification through increasing SOD2 levels [56].…”

Section: Regulatory Mechanisms For Sod2mentioning

confidence: 99%

“…Using cultured VSMCs and calcified aortas from CKD rats, Feng et al disclosed that SIRT3 upregulated Sod2 expressions, attenuated mtROS, and retarded VSMC calcification, while SIRT3 inhibition exhibited the reverse phenotypes [56]. They further discovered that PGC-1α was an important endogenous activator of SIRT3 and could effectively defend against vascular calcification through increasing SOD2 levels [56]. Similarly, PGC-1α overexpression has been shown to upregulate Sod2 and reduce mtROS production, suppressing VSMC migratory ability both in vitro and neointima development in vivo [57].…”

Section: Regulatory Mechanisms For Sod2mentioning

confidence: 99%

Superoxide Dismutase 2 (SOD2) in Vascular Calcification: A Focus on Vascular Smooth Muscle Cells, Calcification Pathogenesis, and Therapeutic Strategies

Tsai

Yeh

Chao

et al. 2021

Oxidative Medicine and Cellular Longevity

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Vascular calcification (VC) describes the pathophysiological phenotype of calcium apatite deposition within the vascular wall, leading to vascular stiffening and the loss of compliance. VC is never benign; the presence and severity of VC correlate closely with the risk of myocardial events and cardiovascular mortality in multiple at-risk populations such as patients with diabetes and chronic kidney disease. Mitochondrial dysfunction involving each of vascular wall constituents (endothelia and vascular smooth muscle cells (VSMCs)) aggravates various vascular pathologies, including atherosclerosis and VC. However, few studies address the pathogenic role of mitochondrial dysfunction during the course of VC, and mitochondrial reactive oxygen species (ROS) seem to lie in the pathophysiologic epicenter. Superoxide dismutase 2 (SOD2), through its preferential localization to the mitochondria, stands at the forefront against mitochondrial ROS in VSMCs and thus potentially modifies the probability of VC initiation or progression. In this review, we will provide a literature-based summary regarding the relationship between SOD2 and VC in the context of VSMCs. Apart from the conventional wisdom of attenuating mitochondrial ROS, SOD2 has been found to affect mitophagy and the formation of the autophagosome, suppress JAK/STAT as well as PI3K/Akt signaling, and retard vascular senescence, all of which underlie the beneficial influences on VC exerted by SOD2. More importantly, we outline the therapeutic potential of a novel SOD2-targeted strategy for the treatment of VC, including an ever-expanding list of pharmaceuticals and natural compounds. It is expected that VSMC SOD2 will become an important druggable target for treating VC in the future.

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Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Inhibits Vascular Calcification Through Sirtuin 3-Mediated Reduction of Mitochondrial Oxidative Stress

Cited by 37 publications

References 57 publications

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

SIRT3 Regulation of Mitochondrial Quality Control in Neurodegenerative Diseases

Superoxide Dismutase 2 (SOD2) in Vascular Calcification: A Focus on Vascular Smooth Muscle Cells, Calcification Pathogenesis, and Therapeutic Strategies

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