Biology subjects

Djukovic, D.

Publications and source records attributed to Djukovic, D..

5 recordsLinked to original sources

bioRxiv2025

Multi-omic integration reveals dynamic changes in human placental metabolism across gestation

ObjectivesMetabolic demands of the developing conceptus are highly dynamic during pregnancy. While placental metabolism has been well described at term and in cell lines, changes in the placental metabolome during development remains understudied. We investigated the placental metabolome, metabolite trajectories, and altered pathways across trimesters in normal human pregnancy by integrating metabolomic and transcriptomic data. MethodsTargeted aqueous metabolomic profiling of 372 metabolites was conducted on placental biopsies from samples collected in the first (n=12), second (n=13), and third (n=11) trimesters of normal pregnancy using liquid chromatography-tandem mass spectrometry. Robust linear models identified differentially abundant metabolites across trimesters in models adjusted for fetal sex and total protein. We conducted pathway analysis using a human metabolic reconstruction. To further aid in biological interpretation, we leveraged publicly available transcriptomics data to conduct pathway-level multi-omic integration throughout gestation. ResultsSamples clustered by trimester in principal component analysis and we identified 5 metabolite trajectories. Out of 193 detectable metabolites, 149 (77%) differed by trimester (FDR<0.05). Using pathway-level multi-omic integration, pathways involved in extracellular transport, and pyruvate, amino acid, NAD, and membrane lipid metabolism are up-regulated in the second trimester compared to the first. In the late third trimester, pathways involved in amino acid metabolism, redox balance, mitochondrial transport, and biomolecule synthesis were down-regulated compared to second trimester. ConclusionsPlacental metabolite abundances change substantially across gestation and integration with metabolic gene expression provides insight into dynamic metabolic function during pregnancy. Observed pathway-level changes potentially reflect the metabolic response to invading maternal circulation in the first-to-second trimester transition, as well as changing maternal and fetal metabolic requirements. Differences observed at term may reflect placental senescence and preparation for parturition. These data can inform other molecular analyses of the placenta by providing enhanced resolution of metabolic changes across pregnancy.

systems biology↗

bioRxiv2025

Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Studies have often equated the effects of knocking down one synthase with broader SAM-dependent outcomes such as histone methylation or phosphatidylcholine (PC) production. Humans and many other organisms express multiple SAM synthases. Evidence in Caenorhabditis elegans, which possesses four SAM synthase genes, suggest that the enzymatic source of SAM impacts its function. For instance, loss of sams-1 leads to enhanced heat shock survival and increased lifespan, whereas reducing sams-4 adversely affects heat stress survival. Here, we show that SAMS-1 contributes to a variety of intermediary metabolic pathways, whereas SAMS-4 is more important to generate SAM for methylation reactions. We demonstrate that loss of sams-1 exerts age-dependent effects on nuclear-encoded mitochondrial gene expression, mitochondrial metabolites, and may induce mitophagy. We propose a mechanistic model where reduced SAM from SAMS-1 acts through PC to impact mitochondria, thereby enhancing survival during heat stress.

cell biology↗

bioRxiv2024

Protein catabolites as blood-based biomarkers of aging physiology: Findings from the Dog Aging Project

Our understanding of age-related physiology and metabolism has grown through the study of systems biology, including transcriptomics, single-cell analysis, proteomics and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers and to develop aging interventions that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) is designed to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs. Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP. By incorporating extensive metadata and whole genome sequencing information, we were able to overcome the limitations inherent in breed-based estimates of genetic and physiological effects, and to probe the physiological and dietary basis of the age-related metabolome. We identified a significant effect of age on approximately 40% of measured metabolites. Among other insights, we discovered a potentially novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which can only be generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. Clinical measures of kidney function mediated about half of the higher ptmAA levels in older dogs. This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.

systems biology↗

bioRxiv2024

Selection for early reproduction leads to accelerated aging and extensive metabolic remodeling in Drosophila melanogaster populations

Experimental evolution studies that feature selection on life-history characters are a proven approach for studying the evolution of aging and variation in rates of senescence. Recently, the incorporation of genomic and transcriptomic approaches into this framework has led to the identification of hundreds of genes associated with different aging patterns. However, our understanding of the specific molecular mechanisms underlying these aging patterns remains limited. Here, we incorporated extensive metabolomic profiling into this framework to generate mechanistic insights into aging patterns in Drosophila melanogaster. Specifically, we characterized metabolomic change over adult lifespan in populations of D. melanogaster where selection for early reproduction has led to an accelerated aging phenotype relative to their controls. Using these data we: i) evaluated evolutionary repeatability across the metabolome; ii) assessed the value of the metabolome as a predictor of "biological age" in this system; and iii) identified specific metabolites associated with accelerated aging. Generally, our findings suggest that selection for early reproduction resulted in highly repeatable alterations to the metabolome and the metabolome itself is a reliable predictor of "biological age". Specifically, we find clusters of metabolites that are associated with the different rates of senescence observed between our accelerated aging population and their controls, adding new insights into the metabolites that may be driving the accelerated aging phenotype. SignificanceWhile experimental evolution studies featuring Drosophila melanogaster have generated significant insights into the forces that shape aging and life history patterns, more recent efforts incorporating genomic and transcriptomic data have had comparatively little success identifying the molecular mechanisms underlying these patterns. Here we work to incorporate molecular phenotyping into this general framework as a way forward. Specifically, we characterize how the metabolome changes with age in populations of D. melanogaster where hundreds of generations of selection for early reproduction have led to enrichment for an accelerated aging phenotype. By comparing to control populations, we show that the metabolome does appear to capture true signals of "biological age" and provides a new avenue for understanding the factors that underlie complex trait variation in real populations.

evolutionary biology↗

bioRxiv2023

Age and sex dependent effects of metabolic response to muscle contraction

Sarcopenia, the age-related loss of muscle mass and function, contributes to decreased quality of life in the elderly and increased healthcare costs. Decreased skeletal muscle mass, specific force, increased overall fatty depositions in the skeletal muscle, frailty and depressed energy maintenance are all associated with increased oxidative stress and the decline in mitochondrial function with age. We hypothesized that elevated mitochondrial stress with age alters the capacity of mitochondria to utilize different substrates following muscle contraction. To test this hypothesis, we designed two in vivo muscle-stimulation protocols to simulate high-intensity intervals (HII) or low intensity steady-state (LISS) exercise to characterize the effect of age and sex on mitochondrial substrate utilization in skeletal muscle following muscle contraction. Following HII stimulation, mitochondria from young skeletal muscle increased fatty acid oxidation compared to non-stimulated control muscle; however, mitochondria from aged muscle decreased fatty acid oxidation. In contrast, following LISS, mitochondrial from young skeletal muscle decreased fatty acid oxidation, whereas aged mitochondria increased fatty acid oxidation. We also found that HII can inhibit mitochondrial oxidation of glutamate in both stimulated and non-stimulated aged muscle, suggesting HII initiates circulation of an exerkine capable of altering whole-body metabolism. Analyses of the muscle metabolome indicates that changes in metabolic pathways induced by HII and LISS contractions in young muscle are absent in aged muscle. Treatment with elamipretide, a mitochondrially targeted peptide, restored glutamate oxidation and metabolic pathway changes following HII suggesting rescuing redox status and improving mitochondrial function in aged muscle enhances the metabolic response to muscle contraction. Statements and DeclarationsThe authors declare no competing financial interests.

physiology↗