Paul Grimsrud

Journal Article Cell Metab · June 6, 2023 Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the β-oxidation pathw ... Full text Link to item Cite

HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis.

Journal Article JCI Insight · January 10, 2023 Carbohydrate response element-binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associat ... Full text Link to item Cite

Proteomics and phosphoproteomics datasets of a muscle-specific STIM1 loss-of-function mouse model.

Journal Article Data Brief · June 2022 STIM1 is an ER/SR transmembrane protein that interacts with ORAI1 to activate store operated Ca2+ entry (SOCE) upon ER/SR depletion of calcium. Normally highly expressed in skeletal muscle, STIM1 deficiency causes significant changes to mitochondrial ultra ... Full text Link to item Cite

Mitochondrial lysine acylation and cardiometabolic stress: truth or consequence?

Journal Article Current Opinion in Physiology · June 1, 2022 Disruptions in oxidative metabolism are often accompanied by tissue accumulation of catabolic carbon intermediates, including acyl CoA molecules that can react with the epsilon amino group of lysine residues on cellular proteins. In general, acyl-lysine po ... Full text Cite

Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Journal Article Nat Commun · May 10, 2022 Statins are a class of drug widely prescribed for the prevention of cardiovascular disease, with pleiotropic cellular effects. Statins inhibit HMG-CoA reductase (HMGCR), which converts the metabolite HMG-CoA into mevalonate. Recent discoveries have shown H ... Full text Link to item Cite

Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice.

Journal Article J Biol Chem · April 2022 A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be none ... Full text Link to item Cite

Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis, and lean mass.

Journal Article Mol Metab · March 2022 OBJECTIVE: Stromal interaction molecule 1 (STIM1) is a single-pass transmembrane endoplasmic/sarcoplasmic reticulum (E/SR) protein recognized for its role in a store operated Ca2+ entry (SOCE), an ancient and ubiquitous signaling pathway. Whereas STIM1 is ... Full text Open Access Link to item Cite

Nicotinamide riboside supplementation confers marginal metabolic benefits in obese mice without remodeling the muscle acetyl-proteome.

Journal Article iScience · January 21, 2022 Nicotinamide riboside supplements (NRS) have been touted as a nutraceutical that promotes cardiometabolic and musculoskeletal health by enhancing nicotinamide adenine dinucleotide (NAD+) biosynthesis, mitochondrial function, and/or the activities of NAD-de ... Full text Link to item Cite

Chronic caloric restriction maintains a youthful phosphoproteome in aged skeletal muscle.

Journal Article Mech Ageing Dev · April 2021 Caloric restriction (CR) can prolong aged skeletal muscle function, yet the molecular mechanisms are not completely understood. We performed phosphoproteomic analysis on muscle from young and old mice fed an ad libitum diet, and old mice fed a CR diet. CR ... Full text Link to item Cite

Sirtuin 5 Is Regulated by the SCFCyclin F Ubiquitin Ligase and Is Involved in Cell Cycle Control.

Journal Article Mol Cell Biol · January 25, 2021 The ubiquitin-proteasome system is essential for cell cycle progression. Cyclin F is a cell cycle-regulated substrate adapter F-box protein for the Skp1, CUL1, and F-box protein (SCF) family of E3 ubiquitin ligases. Despite its importance in cell cycle pro ... Full text Link to item Cite

Extreme Acetylation of the Cardiac Mitochondrial Proteome Does Not Promote Heart Failure.

Journal Article Circ Res · September 25, 2020 RATIONALE: Circumstantial evidence links the development of heart failure to posttranslational modifications of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that Kac compromises mitochondrial performance remains ... Full text Link to item Cite

Disruption of Acetyl-Lysine Turnover in Muscle Mitochondria Promotes Insulin Resistance and Redox Stress without Overt Respiratory Dysfunction.

Journal Article Cell Metab · January 7, 2020 This study sought to examine the functional significance of mitochondrial protein acetylation using a double knockout (DKO) mouse model harboring muscle-specific deficits in acetyl-CoA buffering and lysine deacetylation, due to genetic ablation of carnitin ... Full text Link to item Cite

Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics.

Journal Article Cell Rep · February 5, 2019 Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs ... Full text Link to item Cite

Ablation of Sirtuin5 in the postnatal mouse heart results in protein succinylation and normal survival in response to chronic pressure overload.

Journal Article J Biol Chem · July 6, 2018 Mitochondrial Sirtuin 5 (SIRT5) is an NAD+-dependent demalonylase, desuccinylase, and deglutarylase that controls several metabolic pathways. A number of recent studies point to SIRT5 desuccinylase activity being important in maintaining cardiac function a ... Full text Link to item Cite

Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or β Cell Metabolism in the Absence of Overnutrition.

Journal Article Cell Rep · July 3, 2018 SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial ... Full text Link to item Cite

Integration of BCAA and Lipid Metabolism by the BCKDH Kinase and Phosphatase

Conference Diabetes · July 1, 2018 Strong associations exist between branched chain amino acids (BCAA) and dysregulated glucose and lipid metabolism, but underlying mechanisms are not well understood. One factor contributing to elevated BCAA in obesity is inhibitory phosphorylation ... Full text Cite

The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.

Journal Article Cell Metab · June 5, 2018 Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that r ... Full text Link to item Cite

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model.

Journal Article JCI Insight · July 20, 2017 Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which ... Full text Link to item Cite

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.

Journal Article Cell Metab · April 4, 2017 Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control h ... Full text Link to item Cite

Cysteine S-acetylation is a post-translational modification involved in metabolic regulation.

Preprint · May 21, 2024 Full text Link to item Cite

Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.

HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis.

Proteomics and phosphoproteomics datasets of a muscle-specific STIM1 loss-of-function mouse model.

Mitochondrial lysine acylation and cardiometabolic stress: truth or consequence?

Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice.

Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis, and lean mass.

Nicotinamide riboside supplementation confers marginal metabolic benefits in obese mice without remodeling the muscle acetyl-proteome.

Chronic caloric restriction maintains a youthful phosphoproteome in aged skeletal muscle.

Sirtuin 5 Is Regulated by the SCFCyclin F Ubiquitin Ligase and Is Involved in Cell Cycle Control.

Extreme Acetylation of the Cardiac Mitochondrial Proteome Does Not Promote Heart Failure.

Disruption of Acetyl-Lysine Turnover in Muscle Mitochondria Promotes Insulin Resistance and Redox Stress without Overt Respiratory Dysfunction.

Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics.

Ablation of Sirtuin5 in the postnatal mouse heart results in protein succinylation and normal survival in response to chronic pressure overload.

Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or β Cell Metabolism in the Absence of Overnutrition.

Integration of BCAA and Lipid Metabolism by the BCKDH Kinase and Phosphatase

The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model.

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.

A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation.

Journal Article Cell Metab · April 4, 2017 The mechanisms underlying the formation of acyl protein modifications remain poorly understood. By investigating the reactivity of endogenous acyl-CoA metabolites, we found a class of acyl-CoAs that undergo intramolecular catalysis to form reactive interme ... Full text Link to item Cite

Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation.

Journal Article Cell Rep · November 1, 2016 Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part by increasi ... Full text Link to item Cite

Regulation of Carnitine Acetyltransferase by Lysine Acetylation

Conference DIABETES · June 1, 2016 Link to item Cite

The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins.

Journal Article Cell Rep · January 12, 2016 Lysine acetylation (AcK), a posttranslational modification wherein a two-carbon acetyl group binds covalently to a lysine residue, occurs prominently on mitochondrial proteins and has been linked to metabolic dysfunction. An emergent theory suggests mitoch ... Full text Link to item Cite

Mitochondrial DNA variant in COX1 subunit significantly alters energy metabolism of geographically divergent wild isolates in Caenorhabditis elegans.

Journal Article J Mol Biol · May 29, 2014 Mitochondrial DNA (mtDNA) sequence variation can influence the penetrance of complex diseases and climatic adaptation. While studies in geographically defined human populations suggest that mtDNA mutations become fixed when they have conferred metabolic ca ... Full text Link to item Cite

Quantification of mitochondrial acetylation dynamics highlights prominent sites of metabolic regulation.

Journal Article J Biol Chem · September 6, 2013 Lysine acetylation is rapidly becoming established as a key post-translational modification for regulating mitochondrial metabolism. Nonetheless, distinguishing regulatory sites from among the thousands identified by mass spectrometry and elucidating how t ... Full text Link to item Cite

A quantitative map of the liver mitochondrial phosphoproteome reveals posttranslational control of ketogenesis.

Journal Article Cell Metab · November 7, 2012 Mitochondria are dynamic organelles that play a central role in a diverse array of metabolic processes. Elucidating mitochondrial adaptations to changing metabolic demands and the pathogenic alterations that underlie metabolic disorders represent principal ... Full text Link to item Cite

A proteogenomic survey of the Medicago truncatula genome.

Journal Article Mol Cell Proteomics · October 2012 Peptide sequencing by computational assignment of tandem mass spectra to a database of putative protein sequences provides an independent approach to confirming or refuting protein predictions based on large-scale DNA and RNA sequencing efforts. This use o ... Full text Link to item Cite

Rapid phosphoproteomic and transcriptomic changes in the rhizobia-legume symbiosis.

Journal Article Mol Cell Proteomics · September 2012 Symbiotic associations between legumes and rhizobia usually commence with the perception of bacterial lipochitooligosaccharides, known as Nod factors (NF), which triggers rapid cellular and molecular responses in host plants. We report here deep untargeted ... Full text Link to item Cite

Leveraging proteomics to understand plant-microbe interactions.

Journal Article Front Plant Sci · 2012 Understanding the interactions of plants with beneficial and pathogenic microbes is a promising avenue to improve crop productivity and agriculture sustainability. Proteomic techniques provide a unique angle to describe these intricate interactions and tes ... Full text Link to item Cite

Medicago PhosphoProtein Database: a repository for Medicago truncatula phosphoprotein data.

Journal Article Front Plant Sci · 2012 The ability of legume crops to fix atmospheric nitrogen via a symbiotic association with soil rhizobia makes them an essential component of many agricultural systems. Initiation of this symbiosis requires protein phosphorylation-mediated signaling in respo ... Full text Link to item Cite

X-ray crystallographic analysis of adipocyte fatty acid binding protein (aP2) modified with 4-hydroxy-2-nonenal.

Journal Article Protein Sci · August 2010 Fatty acid binding proteins (FABP) have been characterized as facilitating the intracellular solubilization and transport of long-chain fatty acyl carboxylates via noncovalent interactions. More recent work has shown that the adipocyte FABP is also covalen ... Full text Link to item Cite

Downregulation of adipose glutathione S-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction.

Journal Article Diabetes · May 2010 OBJECTIVE: Peripheral insulin resistance is linked to an increase in reactive oxygen species (ROS), leading in part to the production of reactive lipid aldehydes that modify the side chains of protein amino acids in a reaction termed protein carbonylation. ... Full text Link to item Cite

Phosphoproteomics for the masses.

Journal Article ACS Chem Biol · January 15, 2010 Protein phosphorylation serves as a primary mechanism of signal transduction in the cells of biological organisms. Technical advancements over the last several years in mass spectrometry now allow for the large-scale identification and quantitation of in v ... Full text Link to item Cite

Large-scale phosphoprotein analysis in Medicago truncatula roots provides insight into in vivo kinase activity in legumes.

Journal Article Plant Physiol · January 2010 Nitrogen fixation in legumes requires the development of root organs called nodules and their infection by symbiotic rhizobia. Over the last decade, Medicago truncatula has emerged as a major model plant for the analysis of plant-microbe symbioses and for ... Full text Link to item Cite

Oxidative stress and covalent modification of protein with bioactive aldehydes.

Journal Article J Biol Chem · August 8, 2008 The term "oxidative stress" links the production of reactive oxygen species to a variety of metabolic outcomes, including insulin resistance, immune dysfunction, and inflammation. Antioxidant defense systems down-regulated due to disease and/or aging resul ... Full text Link to item Cite

Carbonylation of adipose proteins in obesity and insulin resistance: identification of adipocyte fatty acid-binding protein as a cellular target of 4-hydroxynonenal.

Journal Article Mol Cell Proteomics · April 2007 Obesity is a state of mild inflammation correlated with increased oxidative stress. In general, pro-oxidative conditions lead to production of reactive aldehydes such as trans-4-hydroxy-2-nonenal (4-HNE) and trans-4-oxo-2-nonenal implicated in the developm ... Full text Link to item Cite

Further insights into quinone cofactor biogenesis: probing the role of mauG in methylamine dehydrogenase tryptophan tryptophylquinone formation.

Journal Article Biochemistry · May 11, 2004 Paracoccus denitrificans methylamine dehydrogenase (MADH) is an enzyme containing a quinone cofactor tryptophan tryptophylquinone (TTQ) derived from two tryptophan residues (betaTrp(57) and betaTrp(108)) within the polypeptide chain. During cofactor format ... Full text Link to item Cite