Regulation of UCP1 and Mitochondrial Metabolism in Brown Adipose Tissue by Reversible Succinylation

Wang, Guoxiao; Meyer, Jesse G.; Cai, Weikang; Softic, Samir; Li, Mengyao Ella; Verdin, Eric; Newgard, Christopher B.; Schilling, Birgit; Kahn, C. Ronald

doi:10.1016/j.molcel.2019.03.021

Cited by 144 publications

(132 citation statements)

References 65 publications

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“…A bunch of mitochondrial proteins have succinylation modification, such as UCP1 in thermogenic function, GLUD1 in glutamate metabolism, SDH in ETC, the TCA cycle, GLS2 and CPS1 in glutaminolysis, ECHA and VLCAD in FAO, HMGCS2 in ketogenesis and SHMT2 in serine catabolism. [229][230][231][232][233] SIRT5-mediated desuccinylation also participates in protection against peroxisome-induced oxidative stress via targeting ACOX1. 230 Moreover, SIRT5 functions as a leading regulator of protein malonylation in both cytosolic metabolisms including glycolysis, gluconeogenesis and mitochondria FAO.…”

Section: Nad + Metabolism In Physiological Functionmentioning

confidence: 99%

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie

Zhang

Gao

et al. 2020

Sig Transduct Target Ther

551

383

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Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

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Section: Nad + Metabolism In Physiological Functionmentioning

confidence: 99%

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie

Zhang

Gao

et al. 2020

Sig Transduct Target Ther

551

383

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“…Samples were analyzed by reverse-phase HPLC-ESI-MS/MS using an Eksigent Ultra Plus nano-LC 2D HPLC system (Dublin, CA) with a cHiPLC system (Eksigent) that was directly connected to a quadrupole TOF TripleTOF 6600 mass spectrometer (SCIEX, Concord, Ontario, Canada) (57,58). After injection, peptide mixtures were loaded onto a C18 pre-column chip (200-m ϫ 0.4-mm ChromXP C18-CL chip, 3 m, 120 Å, SCIEX) and washed at 2 l/min for 10 min with the loading solvent (H 2 O, 0.1% formic acid) for desalting.…”

Section: Mass Spectrometric Analysismentioning

confidence: 99%

Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ

Ebert

Bullard

Basisty

et al. 2020

Journal of Biological Chemistry

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Skeletal muscle atrophy is a highly-prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that aging, fasting, and immobilization promote skeletal muscle atrophy via expression of activating transcription factor 4 (ATF4) in skeletal muscle fibers. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy is unknown. ATF4 is a member of the basic leucine zipper transcription factor (bZIP) superfamily. Because bZIP transcription factors are obligate dimers, and because ATF4 is unable to form highly-stable homodimers, we hypothesized that ATF4 may promote muscle atrophy by forming a heterodimer with another bZIP family member. To test this hypothesis, we biochemically isolated skeletal muscle proteins that associate with the dimerization- and DNA-binding domain of ATF4 (the bZIP domain) in mouse skeletal muscle fibers in vivo. Interestingly, we found that ATF4 forms at least five distinct heterodimeric bZIP transcription factors in skeletal muscle fibers. Furthermore, one of these heterodimers, composed of ATF4 and CCAAT enhancer-binding protein β (C/EBPβ), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4–C/EBPβ heterodimer interacts with a previously unrecognized and evolutionarily conserved ATF–C/EBP composite site in exon 4 of the Gadd45a gene. This three-way interaction between ATF4, C/EBPβ, and the ATF–C/EBP composite site activates the Gadd45a gene, which encodes a critical mediator of muscle atrophy. Together, these results identify a biochemical mechanism by which ATF4 induces skeletal muscle atrophy, providing molecular-level insights into the etiology of skeletal muscle atrophy.

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“…Moreover, succinate post-translationally modifies lysine residues of proteins through succinylation, including L-lactate dehydrogenase A, glyceraldehyde 3-phosphate dehydrogenase, glutamate carrier-1, uncoupling protein-1 and malate dehydrogenase, all enzymes involved in the reprogramming of cancer cell metabolism (68,69).…”

Section: Tca Intermediatesmentioning

confidence: 99%

Nutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness

et al. 2020

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Neoplastic tissues are composed not only by tumor cells but also by several non-transformed stromal cells, such as cancer-associated fibroblasts, endothelial and immune cells, that actively participate to tumor progression. Starting from the very beginning of carcinogenesis, tumor cells, through the release of paracrine soluble factors and vesicles, i.e., exosomes, modify the behavior of the neighboring cells, so that they can give efficient support for cancer cell proliferation and spreading. A mandatory role in tumor progression has been recently acknowledged to metabolic deregulation. Beside undergoing a metabolic reprogramming coherent to their high proliferation rate, tumor cells also rewire the metabolic assets of their stromal cells, educating them to serve as nutrient donors. Hence, an alteration in the composition and in the flow rate of many nutrients within tumor microenvironment has been associated with malignancy progression. This review is focused on metabolic remodeling of the different cell populations within tumor microenvironment, dealing with reciprocal re-education through the symbiotic sharing of metabolites, behaving both as nutrients and as transcriptional regulators, describing their impact on tumor growth and metastasis.

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Regulation of UCP1 and Mitochondrial Metabolism in Brown Adipose Tissue by Reversible Succinylation

Cited by 144 publications

References 65 publications

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ

Nutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness

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