Biology subjects

Kelly, D. P.

Publications and source records attributed to Kelly, D. P..

11 recordsLinked to original sources

bioRxiv2026

Requirement for oxidation of neuronal ketone bodies in aging andneurodegeneration

Glucose is the brains primary fuel, but the brain can also use alternative energy substrates, especially during development or starvation. Emerging evidence suggests ketone metabolism may help the brain adapt to energy stress in neurodegenerative diseases such as Alzheimers disease, although its role in constitutive brain function in normal aging is poorly understood. Using iPSC-derived human neurons and adult-inducible, neuron-specific Bdh1 knockout mice, we show that ketone body metabolism is essential for maximum energy production, neuronal function, and mouse survival--even under normal nutritional conditions. Mechanistically, phenotypes of Bdh1 knockout neurons are mitigated by provision of acetoacetate, a downstream energy metabolite. Moreover, loss of neuronal ketone oxidation markedly increases mortality and memory deficits in Alzheimers disease model mice. These findings identify ketones as critical neuronal fuels, with particular importance during neurodegeneration. While non-energetic activities of ketone bodies are increasingly appreciated, oxidation for energy provision is an essential mechanism for normal function in neurons and mice. Targeting the energetic function of ketones may thus offer new therapeutic strategies for both aging and neurodegenerative diseases such as Alzheimers.

neuroscience↗

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↗

bioRxiv2024

Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel "2-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. Control mice, HFD only, Renin only and HFD-Renin (aka "HFpEF") littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e, IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions. NEW & NOTEWORTHYHeart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.

physiology↗

bioRxiv2024

Sodium-glucose co-transporter 2 Inhibitors Act Independently of SGLT2 to Confer Benefit for Heart Failure with Reduced Ejection Fraction in Mice

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are novel, potent heart failure medications with an unknown mechanism of action. We sought to determine if the beneficial actions of SGLT2i in heart failure were on- or off-target, and related to metabolic reprogramming, including increased lipolysis and ketogenesis. The phenotype of mice treated with empagliflozin and genetically engineered mice constitutively lacking SGLT2 mirrored metabolic changes seen in human clinical trials (including reduced blood glucose, increased ketogenesis, and profound glucosuria). In a mouse heart failure model, SGLT2i treatment, but not generalized SGLT2 knockout, resulted in improved systolic function and reduced pathologic cardiac remodeling. SGLT2i treatment of the SGLT2 knockout mice sustained the cardiac benefits, demonstrating an off-target role for these drugs. This benefit is independent of metabolic changes, including ketosis. The mechanism of action and target of SGLT2i in HF remain elusive.

physiology↗

bioRxiv2023

MBNL1 regulates programmed postnatal switching between regenerative and differentiated cardiac states.

Discovering determinants of cardiomyocyte maturity and the maintenance of differentiated states is critical to both understanding development and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Here, the RNA binding protein Muscleblind-like 1 (MBNL1) was identified as a critical regulator of cardiomyocyte differentiated states and their regenerative potential through transcriptome-wide control of RNA stability. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, whereas loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of the estrogen-related receptor signaling axis was essential for maintaining cardiomyocyte maturity. In accordance with these data, modulating MBNL1 dose tuned the temporal window of cardiac regeneration, where enhanced MBNL1 activity arrested myocyte proliferation, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. Collectively these data suggest MBNL1 acts as a transcriptome-wide switch between regenerative and mature myocyte states postnatally and throughout adulthood.

cell biology↗

bioRxiv2022

A human mitofusin 2 mutation causes mitophagic cardiomyopathy

Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is ~20x over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of the MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical and functional characteristics of MFN2 Q400 versus wild-type and representative CMT2A-causing MFN2 mutants. All MFN2 mutants we studied suppressed mitochondrial fusion, the canonical MFN2 function. Compared to CMT2A mutants MFN2 R94Q and T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 Q400 had normal GTPase activity with impaired conformational shifting. GTPase-defective MFN2 mutants, but not MFN2 Q400, suppressed mitochondrial motility, provoked mitochondrial depolarization and reduced mitochondrial respiration. By contrast, MFN2 Q400 was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse Mfn2 gene induced perinatal cardiomyopathy with no other organ involvement. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cardiomyoblasts expressing MFN2 Q400 exhibited multiple mitophagy defects, but normal mitochondrial respiration. MFN2 Q400 is the first known natural mitophagy- and shape change-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for its enrichment in clinical cardiomyopathy.

developmental biology↗

bioRxiv2022

Ketone body metabolism declines with age in mice in a sex-dependent manner

Understanding how our cells maintain energy homeostasis has long been a focus of aging biology. A decline in energy metabolism is central to many age-related diseases such as Alzheimers disease, heart failure, frailty, and delirium. Intervening on pathways involved in energy homeostasis can extend healthy lifespan. When the primary energy substrate glucose is scarce, mice and humans can partially switch cellular energetic needs to fat-derived ketone bodies (i.e., beta-hydroxybutyrate (BHB), acetoacetate, acetone). Aging is associated with glucose intolerance and insulin insensitivity, yet, surprisingly, what role ketone body metabolism might play in compensating for impaired glucose utilization in age-related diseases is understudied. Here, we investigate how endogenous ketone body production and utilization pathways are modulated by age across the lifespan of male and female C57BL/6N mice (3 mo old, 12 mo old, 22 mo old). We show how different ages have different metabolic and gene expression responses to 1-week ketogenic diet (KD). We hypothesized that there would be a compensatory ketogenic response with age but instead saw declines in plasma BHB concentrations under fasting and non-fasting conditions with strong sexual dimorphism. Under KD, both sexes increased BHB concentrations at all ages, but only males showed strong gene expression induction. We also observed tissue-specific changes with age in baseline ketone metabolism, and surprising induction of extrahepatic ketogenic genes under KD. We found significant residual blood concentrations of BHB in KD even after a knockout of liver BHB production. Overall, these findings show that older mice have impaired non-fasting ketogenesis but are capable of increasing their ketogenic capacity under stimulation (i.e., KD) to meet energetic demands in aging. Therapies to augment non-fasting ketogenesis or provide exogenous ketones may be useful to improve energy homeostasis in diseases and conditions of aging.

physiology↗

bioRxiv2022

Ketolysis is a metabolic driver of CD8+ T cell effector function through histone acetylation

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. However, the metabolic pathways critical for optimal T cell responses remain poorly understood. Here, we identify ketone bodies (KBs) - including {beta}-hydroxybutyrate ({beta}OHB) and acetoacetate (AcAc) - as essential fuels supporting CD8+ T cell metabolism and effector function. Ketolysis is an intrinsic feature of highly functional CD8+ T effector (Teff) cells and {beta}OHB directly increases CD8+ Teff cell IFN-{gamma} production and cytolytic activity. Using metabolic tracers, we establish that CD8+ Teff cells preferentially use KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boost the respiratory capacity of CD8+ T cells and TCA cycle-dependent metabolic pathways that fuel T cell growth. Mechanistically, we find that {beta}OHB is a major substrate for acetyl-CoA production in CD8+ T cells and regulates effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses. One Sentence summaryKetone bodies promote CD8+ T cell metabolism and effector function through regulation of epigenetic programming

immunology↗

bioRxiv2022

Human papilloma virus E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis

Therapy with radiation plus cisplatin kills human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) by increasing reactive oxygen species beyond cellular antioxidant capacity. To explore why some patients fail these standard treatments, we evaluated whether the variation in HPV oncoprotein levels among HPV+ OPSCCs impacts mitochondrial metabolism, a source of antioxidant capacity. In cell line and patient-derived xenograft models, levels of HPV full-length E6 (fl-E6) inversely correlated with oxidative phosphorylation, antioxidant capacity, and therapy resistance, and fl-E6 was the only HPV oncoprotein to display such correlation. Ectopically expressing fl-E6 in models with low levels reduced mitochondrial mass, depleted antioxidant capacity, and sensitized to therapy. In this setting, fl-E6 repressed the PGC-1/ERR pathway for mitochondrial biogenesis by reducing p53-dependent PGC-1 transcription. Concordant observations were made in three clinical cohorts, where expression of mitochondrial components was higher in tumors of patients with reduced survival. These tumors contained the lowest fl-E6 levels, highest p53 target gene expression, and an activated PGC-1/ERR pathway. Our findings demonstrate that E6 can potentiate treatment responses by depleting mitochondrial antioxidant capacity and provide evidence for low E6 negatively impacting patient survival. E6s interaction with the PGC-1/ERR axis has implications for predicting and targeting treatment resistance in OPSCC.

cancer biology↗

bioRxiv2019

Immune, Autonomic, and Endocrine Dysregulation in Autism and Ehlers-Danlos Syndrome/Hypermobility Spectrum Disorders Versus Unaffected Controls

BackgroundA growing body of literature suggests etiological overlap between Ehlers-Danlos syndrome (EDS)/hypermobility spectrum disorders (HSD) and some cases of autism, although this relationship is poorly delineated. In addition, immune, autonomic, and endocrine dysregulation are reported in both conditions and may be relevant to their respective etiologies.\n\nAimsTo study symptom overlap in these two comorbid spectrum conditions.\n\nMethods and ProceduresWe surveyed 702 adults aged 25+ years on a variety of EDS/HSD-related health topics, comparing individuals with EDS/HSD, autism, and unaffected controls.\n\nOutcomes and ResultsThe autism group reported similar though less severe symptomology as the EDS/HSD group, especially in areas of immune/autonomic/endocrine dysregulation, connective tissue abnormalities (i.e., skin, bruising/bleeding), and chronic pain. EDS/HSD mothers with autistic children reported more immune symptoms than EDS/HSD mothers without, suggesting the maternal immune system could play a heritable role in these conditions (p = 0.0119).\n\nConclusions and ImplicationsThese data suggest that EDS/HSD and autism share aspects of immune/autonomic/endocrine dysregulation, pain, and some tissue fragility, which is typically more severe in the former. This overlap, as well as documented comorbidity, suggests some forms of autism may be hereditary connective tissue disorders (HCTD).

neuroscience↗

bioRxiv2017

Metabolite profile and mitochondrial energetics characterize poor early recovery of muscle mass following hind limb unloading in old mice

The progression of age-related sarcopenia can be accelerated by impaired recovery of muscle mass following periods of disuse due to illness or immobilization. The molecular underpinnings of poor recovery of aging muscle following disuse remain largely unknown. However, recent evidence suggests that mitochondrial energetics may play an important role. Here, we report that 22-24 month old mice with low muscle mass and insulin resistance display poor early recovery of muscle mass following 10 days of hind limb unloading. We took an unbiased approach to identify changes in energy metabolism gene expression and metabolite pools and show for the first time that persistent mitochondrial dysfunction, dysregulated fatty acid {beta}-oxidation and elevated H2O2 emission underlie poor early recovery of muscle mass following a period of disuse in old mice. Importantly, this is linked to more severe whole-body insulin resistance. The findings suggest that muscle fuel metabolism and mitochondrial energetics should be a focus for mining therapeutic targets to improve recovery of muscle mass following periods of disuse in older animals.

physiology↗