Biology subjects

Ahn, B.

Publications and source records attributed to Ahn, B..

6 recordsLinked to original sources

bioRxiv2026

Matched Plasma and Tissue Proteomics Reveal the Selective Nature of Circulating Biomarkers of Human Aging

Aging is systemic, yet how circulating proteins reflect molecular aging within solid tissues remains unclear. We profiled 5,415 proteins using Olink Explore HT in 178 adults aged 20-87 years, including matched plasma-muscle (n = 56) and plasma-ovary (n = 24) pairs. Plasma-tissue concordance was limited, with 50 muscle and 17 ovarian proteins significantly correlated, indicating that plasma selectively reflects tissue protein abundance. Age-correlated proteins and pathways differed markedly across sex and tissue strata, Including immune/inflammatory signatures in female plasma, vascular and extracellular-matrix pathways in male plasma, and collagen remodeling in the ovary. Expression Variation Analysis further revealed predominantly context-specific age-related changes in protein coordination, including FAS/FADD/TRAIL death-receptor networks in plasma and a TP53-CDKN1A senescence-associated axis in muscle. Exploratory multivariate models identified additional plasma associations with subsets of tissue proteins, including tissue-restricted muscle proteins. Together, these findings define plasma as a selective, context-dependent window into human tissue aging.

systems biology↗

bioRxiv2026

Coenzyme A is a redox sensing cofactor for malic enzyme 2 regulating oxidative stress and mitochondrial metabolism

Coenzyme A (CoA) is an essential cofactor required for numerous metabolic reactions, yet its ability to bind and regulate proteins remains poorly defined. Using a proteomic approach, we identified malic enzyme 2 (ME2) as a CoA-binding protein. ME2 uses NAD(P)+ to convert malate to pyruvate, generating NAD(P)H to support energy production and redox homeostasis. ME2 binds CoA at an allosteric site previously thought to bind NAD(P)+. Reduced CoA has minimal effect on ME2 activity, but the oxidized form, CoA disulfide, strongly activates ME2 by promoting ME2 tetramerization and a catalytically efficient closed conformation. Under oxidative stress, ME2 facilitates CoA disulfide formation, enhancing NADPH production and cellular defense against reactive oxygen species (ROS). Mice with ME2 mutation that cannot bind CoA show impaired muscle performance, elevated ROS, and mitochondrial dysfunction. These findings establish CoA as a redox-sensing cofactor, allowing cells to respond to ROS and promote mitochondrial metabolism, and expanding the function of this essential cofactor.

biochemistry↗

bioRxiv2025

Whole body MondoA deletion protects against diet-induced obesity through uncontrolled multi-organ substrate utilization and futile cycling

ObjectiveDelineating the nodal control points that maintain whole-body energy homeostasis is critical for understanding potential treatments of obesity and cardiometabolic diseases. The nutrient-sensing transcription factor MondoA is a regulator of skeletal muscle fuel storage, where muscle-specific inhibition improves glucose tolerance and insulin sensitivity. However, the role of MondoA in whole body energy metabolic homeostasis is not understood. MethodsGeneralized MondoA knockout (gKO) mice were generated and assessed for glucose tolerance and insulin sensitivity, body composition, energy expenditure, cold tolerance, and tissue specific transcriptional changes in response to high fat diet. Complementary studies in cultured human adipocytes assessed the impact of MondoA deficiency on substrate utilization and lipolysis. ResultsgKO mice are protected from diet-induced obesity and insulin resistance, through increased whole body energy expenditure. gKO mice exhibit reduced brown and inguinal white adipose tissue mass, without evidence of beiging. The gKO mice are hyperlactatemic and isolated MondoA-deficient adipocytes have increased 2-deoxyglucose uptake and glycolytic function. Lastly, gKO mice and KO adipocytes display increased circulating glycerol relative to free fatty acids in response to adrenergic stimulus consistent with elevated re-esterification. However, this phenotype is not recapitulated in adipocyte-specific KO mice. ConclusionsMondoA deficiency alters cellular sensing of nutrient availability and storage/utilization mechanisms. In the whole-body setting, this results in increased energy expenditure, potentially related to increased glucose uptake and glycolytic flux driving glycerol synthesis to supply high rates of lipolysis and lipid re-esterification. These results suggest that MondoA functions to maintain fuel storage and when lost, inter-organ futile cycling ensues. O_FIG O_LINKSMALLFIG WIDTH=140 HEIGHT=200 SRC="FIGDIR/small/680559v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1ccf42dorg.highwire.dtl.DTLVardef@b2da28org.highwire.dtl.DTLVardef@1081aforg.highwire.dtl.DTLVardef@1b2168d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO 1) Global MondoA deficiency drives 2) tissue glucose uptake which in skeletal muscle is 3) converted and excreted as lactate, while in adipose tissue 4) triglyceride re-esterification requires 5) de novo glycerol synthesis to feed into the futile cycle. C_FIG

physiology↗

bioRxiv2025

Unacylated Ghrelin Counteracts Contractile and Mitochondrial Dysfunction in Cancer Cachexia

BackgroundCancer cachexia is a complex metabolic syndrome that severely impacts patient mobility, treatment strategies, and quality of life. However, no treatments are available to mitigate the debilitating consequences of cancer cachexia. Unacylated ghrelin (UnAG), the main circulating form of ghrelin, enhances muscle growth and mitochondrial function in various diseases, but its effects in cancer cachexia remain to be tested. MethodsMale C57Bl6/N mice were assigned to one of three treatment groups: non-tumor-bearing (NTB), tumor-bearing (TB), or tumor-bearing treated with unacylated ghrelin (TB+UnAG). Over four weeks, we monitored body weight, food intake, and tumor size. We assessed muscle mass, contractility, mitochondrial oxygen consumption rate (OCR), and reactive oxygen species (ROS) production. Proteomic analysis was performed to elucidate the downstream effects of UnAG. Cell culture assays were performed to measure the in vitro effects of cancer cell-secreted factors and UnAG on myoblasts. ResultsGastrocnemius and quadriceps muscle masses were reduced by 20-30% in TB mice compared to NTB controls; however, UnAG treatment prevented approximately 50% of this loss. Beyond muscle mass, UnAG enhanced the isometric maximum specific force of the extensor digitorum longus by 70% in TB mice. This improvement in muscle quality was associated with preferential upregulation of myosin heavy chain expression in TB+UnAG mice. UnAG also increased mitochondrial OCR while reducing ROS production. Mitochondrial DNA (mtDNA) copy number, which was reduced in TB mice, was restored by UnAG, while the reduced mtDNA mutation frequency in TB mice was maintained with treatment, indicating improved mtDNA integrity. Consistent with enhanced mitochondrial function, treadmill running time was significantly increased in TB+UnAG mice. Proteomic analysis revealed that UnAG downregulated proteins associated with proteolysis, while normalizing antioxidant enzyme thioredoxin and proteins involved in calcium handling. Cancer cell-conditioned medium reduced myotube width in vitro, but UnAG treatment preserved myotube structure.. ConclusionUnAG protects against cancer cachexia by targeting multiple risk factors, including myosin heavy chain expression, mitochondrial bioenergetics, and modulation of protein degradation pathways.

physiology↗

bioRxiv2023

In vivo evolution of a Klebsiella pneumoniae capsule defect promotes complement-mediated opsono-phagocytosis and persistence during recurrent infection

Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) bloodstream infections rarely overwhelm the host but are associated with high mortality. The complement system is a key host defense against bloodstream infection. However, there are varying reports of serum resistance among KPC-Kp isolates. We assessed growth of 59 KPC-Kp clinical isolates in human serum and found increased resistance in 16/59 (27%). We identified five genetically-related bloodstream isolates with varying serum resistance profiles collected from a single patient during an extended hospitalization marked by recurrent KPC-Kp bloodstream infections. We noted a loss-of-function mutation in the capsule biosynthesis gene, wcaJ, that emerged during infection was associated with decreased polysaccharide capsule content, and resistance to complement-mediated killing. Surprisingly, disruption of wcaJ increased deposition of complement proteins on the microbial surface compared to the wild-type strain and led to increased complement-mediated opsono-phagocytosis in human whole blood. Disabling opsono-phagocytosis in the airspaces of mice impaired in vivo control of the wcaJ loss-of-function mutant in an acute lung infection model. These findings describe the rise of a capsular mutation that promotes KPC-Kp persistence within the host by enabling co-existence of increased bloodstream fitness and reduced tissue virulence. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/542722v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@155736eorg.highwire.dtl.DTLVardef@10d47c0org.highwire.dtl.DTLVardef@e1ab83org.highwire.dtl.DTLVardef@1c33131_HPS_FORMAT_FIGEXP M_FIG Graphical abstract Created with BioRender.com C_FIG

microbiology↗

bioRxiv2022

Methamphetamine Self-Administration Differential Effects on Mesolimbic Glutathione Levels, Mitochondrial Respiration, and Dopamine Neuron Firing Activity

Acute and neurotoxic regimens of METH are known to increase reactive oxygen species (ROS), affect redox homeostasis, and lead to cellular damage in dopamine neurons. However, functional changes induced by long-term METH self-administration on mitochondrial respiratory metabolism and redox homeostasis are less known. To fill this gap in our knowledge, we implanted adult mice with a jugular catheter and trained them to nose poke for METH infusions in operant chambers. After completing several weeks of METH self-administration exposure, we collected samples of the ventral striatum (vSTR) and the ventral midbrain (vMB), containing the nucleus accumbens (NAc) and the ventral tegmental area (VTA), respectively. We used HPLC to determine the levels of the ROS scavenger glutathione in its reduced (GSH) and oxidized (GSSG) forms. Then, we used high-resolution respirometry to determine the oxygen consumption rate (OCR) of mitochondrial complexes under several substrates and inhibitors. Finally, we used in vivo single-unit extracellular recordings to assess changes in dopamine neuron firing activity in the VTA. METH self-administration produces a progressive decrease of the GSH pool in vST, which correlates with METH lifetime intake. We observed increased mitochondrial respiration across the two mesolimbic regions, but only vMB OCR correlates with METH lifetime intake. We recorded an increased number of spontaneously active dopamine neurons with decreased firing rate and burst activity in the VTA. METH lifetime intake inversely correlates with firing rate, the percentage of spikes in a burst, and directly correlates with the number of neurons per track. We conclude that METH self-administration progressively decreased the antioxidant pool in sites of higher dopamine release and produced an increased mitochondrial metabolism in the mesolimbic areas, probably derived from the increased number of dopamine neurons actively firing. However, dopamine neuron firing activity is decreased by METH self-administration, reflecting a new basal level of dopamine neurotransmission in response to the prolonged effects of METH on dopamine release and circuitry feedback.

neuroscience↗