Biology subjects

Khetarpal, S. A.

Publications and source records attributed to Khetarpal, S. A..

4 recordsLinked to original sources

bioRxiv2024

Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST

Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From this data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

molecular biology↗

bioRxiv2024

Cardiomyocyte PGC-1α enables physiological adaptations to endurance exercise through suppression of GDF15 and cardiac atrophy

Exercise training induces physiological cardiac hypertrophy, enhanced mitochondrial biogenesis and myocardial contractility. In skeletal muscle, the transcriptional coactivator PGC-1 is a key orchestrator of these responses. The heart expresses abundant and exercise-responsive PGC-1, but it is unclear whether cardiomyocyte PGC-1 is necessary for cardiac adaptation to endurance training. Here we demonstrate that cardiomyocyte PGC-1 is required for physiological cardiac hypertrophy during exercise training in mice. In the absence of cardiomyocyte PGC-1, voluntary wheel running does not improve exercise capacity and instead confers immune-fibrotic-atrophic heart failure after just 6 weeks of training. We identify cardiomyocyte PGC-1 as a negative regulator of stress-responsive senescence gene expression. The most enriched of these is the myomitokine GDF15. GDF15 is secreted locally but not systemically in PGC-1-deficient mouse hearts and reduces cardiomyocyte size. Cardiomyocyte-specific reduction of GDF15 expression preserves exercise tolerance and cardiac contractility in PGC-1-deficient mice during endurance training. Finally, we show that cardiomyocyte PPARGC1A expression correlates with cardiomyocyte number and negatively with GDF15 expression in human cardiomyopathies through single nucleus RNA sequencing. Our data implicate cardiomyocyte PGC-1 as a vital safeguard against stress-induced atrophy and local GDF15-induced dysfunction during exercise.

physiology↗

bioRxiv2020

ApoC-III helical structure determines its ability to bind plasma lipoproteins and inhibit Lipoprotein Lipase-mediated triglyceride lipolysis.

In humans, apolipoprotein C-III (apoC-III) plasma levels have been associated with increased risk of cardiovascular disease. This association is in part explained by the effects of apoC-III on triglyceride (TG) metabolism; apoC-III raises plasma TG by increasing very low density lipoprotein (VLDL) secretion, inhibiting lipoprotein lipase (LPL)-mediated TG lipolysis, and impairing the removal of triglyceride-rich lipoprotein (TRL) remnants from the circulation. In this study, we explored the structure-function relationship the interaction of apoC-III with plasma lipoproteins and its ultimate impact on LPL activity. The structural and functional properties of wild-type (WT) apoC-III were compared with two missense variants previously associated with lower (A23T) and higher (Q38K) plasma TG. ApoC-III in the lipid-free state is unstructured but its helix content and stability increases when bound to lipid. Lipid-bound apoC-III contains two alpha helices spanning residues amino acids 11 - 38 (helix 1) and 44 – 64 (helix 2). Investigation of the structural and functional consequences of the A23T and Q38K variants showed that these amino acid substitutions within helix 1 do not significantly alter the stability of the helical structure but affect its hydrophilic-lipophilic properties. The A23T substitution impairs lipoprotein binding capacity, reduces LPL inhibition, and ultimately leads to lower plasma TG levels. Conversely, the Q to K substitution at position 38 enhances the lipid affinity of helix 1, increases TRL binding capacity and LPL inhibition, and is associated with hypertriglyceridemia. This study indicates that structural modifications that perturb the hydrophilic/lipophilic properties of the alpha helices can modulate the hypertriglyceridemic effects of apoC-III.Competing Interest StatementDJR is a a co-founder of Staten Biotechnology, he is a member of the Scientific Advisory Boards of Alnylam, Novartis, and Pfizer, and he was previously a consultant for Akcea. The other authors declare no competing financial interests.View Full Text

biochemistry↗

bioRxiv2017

Multiplexed targeted resequencing identifies coding and regulatory variation underlying phenotypic extremes of HDL-cholesterol in humans

Genome-wide association studies have uncovered common variants at many loci influencing human complex traits and diseases, such as high-density lipoprotein cholesterol (HDL-C). However, the contribution of the identified genes is difficult to ascertain from current efforts interrogating common variants with small effects. Thus, there is a pressing need for scalable, cost-effective strategies for uncovering causal variants, many of which may be rare and noncoding. Here, we used a multiplexed inversion probe (MIP) target capture approach to resequence both coding and regulatory regions at seven HDL-C associated loci in 797 individuals with extremely high HDL-C vs. 735 low-to-normal HDL-C controls. Our targets included protein-coding regions of GALNT2, APOA5, APOC3, SCARB1, CCDC92, ZNF664, CETP, and LIPG (>9 kb), and proximate noncoding regulatory features (>42 kb). Exome-wide genotyping in 1,114 of the 1,532 participants yielded a >90% genotyping concordance rate with MIP-identified variants in ~90% of participants. This approach rediscovered nearly all established GWAS associations in GALNT2, CETP, and LIPG loci with significant and concordant associations with HDL-C from our phenotypic-extremes design at 0.1% of the sample size of lipid GWAS studies. In addition, we identified a novel, rare, CETP noncoding variant enriched in the extreme high HDL-C group (P<0.01, Score Test). Our targeted resequencing of individuals at the HDL-C phenotypic extremes offers a novel, efficient, and cost-effective approach for identifying rare coding and noncoding variation differences in extreme phenotypes and supports the rationale for applying this methodology to uncover rare variation--particularly non-coding variation--underlying myriad complex traits.

genomics↗