Biology subjects

Bharathi, S.

Publications and source records attributed to Bharathi, S..

10 recordsLinked to original sources

bioRxiv2026

Humanin analogue promotes metabolic reprogramming to protect the ischemic heart

BackgroundMyocardial ischemia drives adverse cardiac remodeling, metabolic inflexibility, and progression to heart failure. Mitochondrial dysfunction and impaired substrate utilization contribute to cardiomyocyte death and fibrosis, particularly with aging. Humanin (HNG), a mitochondria-derived peptide, has been shown to reduce acute ischemic injury, but its role in chronic ischemia and cardiac remodeling remains unknown. MethodsWe investigated the effects of HNG treatment in young and aged murine models of myocardial ischemia without reperfusion. Cardiac function and structure were assessed by echocardiography and molecular markers of remodeling. Myocardial metabolism was interrogated using targeted metabolomics, gene expression, substrate uptake assays, and metabolic flux analyses. Mechanistic studies examined glucose transporter trafficking and protein-protein interactions. ResultsHNG treatment improved cardiac function and significantly attenuated adverse remodeling in both young and old mice. HNG treatment induced marked metabolic reprogramming characterized by reduced myocardial fatty acid content, downregulation of fatty acid uptake and oxidation pathways, and decreased oxidative stress. Importantly, these changes were accompanied by enhanced glucose oxidation, increased tricarboxylic acid cycle flux, improved coupling of glycolysis to mitochondrial oxidation, and increased ATP production. Time-course studies demonstrated that increased glucose oxidation preceded reductions in fatty acid oxidation, indicating a primary role for glucose metabolism in HNG-mediated cardioprotection. Mechanistically, we identified vesicle-associated membrane protein 7 (VAMP7) as a novel binding partner of HNG, and that this interaction is required for GLUT4 translocation to the plasma membrane and HNG-induced ATP generation. ConclusionsHNG protects the ischemic heart by promoting metabolic reprogramming that shifts substrate utilization from fatty acids to glucose and limiting maladaptive remodeling. These findings identify HNG as a novel regulator of cardiac metabolism and a potential therapeutic strategy for ischemic heart failure. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/732776v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1929de8org.highwire.dtl.DTLVardef@bcf254org.highwire.dtl.DTLVardef@c99b70org.highwire.dtl.DTLVardef@1fc08bb_HPS_FORMAT_FIGEXP M_FIG C_FIG What are the clinical implications?Heart failure (HF) is a major global health concern, affecting over 6.7 million adults in the United States alone, with projections to exceed 11 million by 2050. Myocardial infarction (MI) is a leading cause of HF. Despite substantial advances in acute MI care, survivors remain at high risk for adverse cardiac remodeling and chronic HF, especially in the elderly. We report here that treatment with a potent analog of Humanin (HN), an endogenous mitochondria-associated peptide, decreases infarct size, decreases fibrosis and improves cardiac function following cardiac ischemia induced by permanent ligation of coronary artery in both young and aged mice. These effects are associated with changes in cardiac metabolism, oxidative stress, and remodeling. HN and analogs have been shown to be beneficial in many age-related diseases. The endogenous origin of Humanin, its favorable safety profile in preclinical studies and its pleiotropic effects support targeting HNG as a promising therapeutic strategy for ischemic heart disease and post-myocardial infarction heart failure in humans.

Systems Biology↗

bioRxiv2026

In Vivo 4D Oxy-Wavelet MRI as a Non-Invasive Biomarker of Brain Mitochondrial Function across the Lifespan

Mitochondria are essential for cellular energy production and are particularly critical for brain development and function. Neurons rely predominantly on oxidative phosphorylation for energy production, rendering the brain highly vulnerable to mitochondrial dysfunction. Consequently, impaired mitochondrial function contributes to a broad spectrum of neurological and systemic disorders, making mitochondria attractive therapeutic targets. Despite this importance, there is currently no non-invasive, spatially resolved method to assess mitochondrial function in the intact living brain. Here, we establish a non-invasive functional MRI approach--4D Oxy-wavelet MRI--to probe in vivo mitochondrial electron transport chain (ETC) function in a spatially specific manner across the lifespan, from fetal to adult brains. This method employs a low-rank k-t sub-Nyquist acquisition strategy to achieve simultaneous structural and functional imaging with high spatial (78 m) and temporal ([~]14 ms) resolution, enabling motion-robust imaging in multi-fetal mouse pregnancies. Mitochondrial ETC function is interrogated by measuring oxygen homeostasis responses to brief hypoxic challenges, analyzed using computational time-frequency wavelet profiling. We validate this approach in mouse models of mitochondrial respiratory chain disease and late-onset Alzheimers disease, from in utero fetuses to adults, and demonstrate reproducibility and specificity using pharmacological hyperemia and ETC complex I inhibition. We further show parallel wavelet responses in placenta and fetal brain, enabling multi-organ interrogation of the placenta-brain axis. Finally, we present first-in-human feasibility data, supporting translational potential for non-invasive assessment of mitochondrial function in living brains across the lifespan.

bioengineering↗

bioRxiv2025

Systemic Metabolic Rewiring in a Mouse Model of Left Ventricular Hypertrophy

Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall, and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). Development of therapies to increase and enhance LFCA FAO are underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, Myosin binding protein-C3 (Mybpc3), resulted in depletion of adipose tissue, decreased mitochondrial function in skeletal muscle, increased lipid accumulation in both heart and liver, and loss of whole-body metabolic flux. We found that supplementation of exogenous LCFAs boosted LVH mitochondrial function and reversed cardiac lipid accumulation, but did not fully reverse the hypertrophied heart nor systemic metabolic phenotypes. This study indicates that the LVH phenotype caused systemic metabolic rewiring in Mybpc3-/- mice, and that exogenous LCFA supplementation boosted mitochondrial function in both cardiac and skeletal muscle.

physiology↗

bioRxiv2025

Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders

Long-chain fatty acid oxidation disorders (LC-FAODs) cause energy deficits in heart and skeletal muscle that is only partially corrected by current medium-chain lipid therapies such as triheptanoin. We find that heart and muscle lack medium-chain acyl-CoA synthetases, limiting the capacity for {beta}-oxidation of medium-chain fatty acids. Instead, heart and muscle mitochondria robustly respire on medium-chain acylcarnitines. The mitochondrial matrix enzyme carnitine acetyltransferase (CrAT) efficiently converts orally delivered octanoylcarnitine (C8-carnitine) to octanoyl-CoA for energy generation. C8-carnitine exhibits twice the oral bioavailability of triheptanoin and distributes to muscle and heart. A single oral dose markedly enhances grip strength, basal locomotion, and treadmill endurance while attenuating lactate and creatine kinase elevations in multiple mouse models of LC-FAODs. Thus, medium-chain acylcarnitines overcome a previously unrecognized metabolic bottleneck in LC-FAOD muscle and may represent an alternative to triglyceride-based therapies for bioenergetic disorders.

biochemistry↗

bioRxiv2025

Odd-chain dicarboxylic acid feeding recapitulates the biochemical phenotype of glutaric aciduria type-1 in mice

Glutaric aciduria type-1 (GA1) is an inherited mitochondrial neurometabolic disorder with a poorly understood pathogenesis and unmet medical needs. GA1 can be diagnosed via its hallmark biochemical signature consisting of glutaric aciduria, 3-hydroxyglutaric aciduria, and increased plasma glutarylcarnitine. These glutaryl-CoA-derived metabolites are thought to originate solely in the mitochondria. Here, we demonstrate that wild-type mice fed an 11-carbon odd-chain dicarboxylic acid (undecanedioic acid, DC11) recreates the biochemical phenotype of GA1. Odd-chain dicarboxylic acids like DC11 are not present in food but can arise from several endogenous processes, such as lipid peroxidation and fatty acid {omega}-oxidation. DC11 is chain-shortened in peroxisomes to glutaryl (DC5)-CoA, which then gives rise to the GA1-like pattern of DC5 metabolites in urine, tissues, and blood. Glutaric acid released from peroxisomes during DC11 chain-shortening can enter mitochondria, be activated to CoA by the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT), and become substrate for glutaryl-CoA dehydrogenase (GCDH), the enzyme that is mutated in GA1. Our data provide proof-of-concept that the generation of dicarboxylic acids by {omega}-oxidation, which is stimulated during the same catabolic states known to trigger acute encephalopathy in GA1, may exacerbate disease by increasing the glutaryl-CoA substrate load in mitochondria.

biochemistry↗

bioRxiv2024

Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury

Proximal tubular epithelial cells (PTECs) are particularly vulnerable to acute kidney injury (AKI). While fatty acids are the preferred energy source for PTECs via fatty acid oxidation (FAO), FAO-mediated H2O2 production in mitochondria has been shown to be a major source of oxidative stress. We have previously shown that a mitochondrial flavoprotein, long-chain acyl-CoA dehydrogenase (LCAD), which catalyzes a key step in mitochondrial FAO, directly produces H2O2 in vitro. Further we have established that loss of a lysine deacylase, Sirtuin 5 (Sirt5-/-), induces hypersuccinylation and inhibition of mitochondrial FAO genes to stimulate peroxisomal FAO and to protect against AKI. However, the role of LCAD has yet to be determined. Mass spectrometry data acquisition revealed that LCAD is hypersuccinylated in Sirt5-/- kidneys after AKI. Following two distinct models of AKI, cisplatin treatment or renal ischemia/reperfusion (IRI), LCAD knockout mice (LCAD-/-) demonstrated renoprotection against AKI. Specifically, LCAD-/- kidneys displayed mitigated renal tubular injury, decreased oxidative stress, preserved mitochondrial function, enhanced peroxisomal FAO, and decreased ferroptotic cell death. LCAD deficiency confers protection against two distinct models of AKI. This suggests a therapeutically attractive mechanism whereby preserved mitochondrial respiration as well as enhanced peroxisomal FAO by loss of LCAD mediates renoprotection against AKI.

pathology↗

bioRxiv2024

Mitigation of Fetal Irradiation Injury from Mid-Gestation Total Body Radiation with Mitochondrial-Targeted GS-Nitroxide JP4-039

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal irradiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal irradiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)- nitroxide radiation mitigator, JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total body ionizing irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time- and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed significant reduction of mitochondrial function in the fetal brain after 3Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. Maternal administration JP4-039 one day after TBI (E14.5), which can pass through the placental barrier, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. This also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. As JP4-039 administration did not change litter sizes or fetus viability, together these findings indicate JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure. One Sentence SummaryMitochondrial-targeted gramicidin S (GS)-nitroxide JP4-039 is safe and effective radiation mitigator for mid-gestational fetal irradiation injury.

developmental biology↗

bioRxiv2023

Adjusted vascular contractility relies on integrity of progranulin pathway: Insights into mitochondrial function

ObjectiveCardiovascular disease (CVD) is a global health crisis and a leading cause of mortality. The intricate interplay between vascular contractility and mitochondrial function is central to CVD pathogenesis. The progranulin gene (GRN) encodes glycoprotein progranulin (PGRN), a ubiquitous molecule with known anti-inflammatory property. However, the role of PGRN in CVD remains enigmatic. In this study, we sought to dissect the significance of PGRN in the regulation vascular contractility and investigate the interface between PGRN and mitochondrial quality. MethodOur investigation utilized aortae from male and female C57BL6/J wild-type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) mice, encompassing wire myograph assays to assess vascular contractility and primary aortic vascular smooth muscle cells (VSMCs) for mechanistic insights. ResultsOur results showed suppression of contractile activity in PGRN-/- VSMCs and aorta, followed by reduced -smooth muscle actin expression. Mechanistically, PGRN deficiency impaired mitochondrial oxygen consumption rate (OCR), complex I activity, mitochondrial turnover, and mitochondrial redox signaling, while restoration of PGRN levels in aortae from PGRN-/- mice via lentivirus delivery ameliorated contractility and boosted OCR. In addition, VSMC overexpressing PGRN displayed higher mitochondrial respiration and complex I activity accompanied by cellular hypercontractility. Furthermore, increased PGRN triggered lysosome biogenesis by regulating transcription factor EB and accelerated mitophagy flux in VSMC, while treatment with spermidine, an autophagy inducer, improved mitochondrial phenotype and enhanced vascular contractility. Finally, angiotensin II failed to induce vascular contractility in PGRN-/- suggesting a key role of PGRN to maintain the vascular tone. ConclusionOur findings suggest that PGRN preserves the vascular contractility via regulating mitophagy flux, mitochondrial complex I activity, and redox signaling. Therefore, loss of PGRN function appears as a pivotal risk factor in CVD development.

pharmacology and toxicology↗

bioRxiv2021

Understanding the complexity of Epimorphic Regeneration in zebrafish: A Transcriptomic and Proteomic approach.

Genomic and Proteomic changes play a crucial role in perpetuating regeneration of complex tissues through differentiation and growth. The complex Epimorphic regeneration of zebrafish caudal fin tissue is hasty and absolute. This study was executed to understand the role of various genes/proteins involved in the regeneration of zebrafish caudal fin tissue through differential expression analysis. High throughput transcriptomics analysis involving Next Generation Sequencing approach and iTRAQ based quantitative proteomics analyses were performed on the regenerating tissue samples for various regenerating time points. Based on our study 1408 genes and 661 proteins were found differentially regulated in the regenerating caudal fin tissue for having at least 1-log fold change in their expression at 12hpa, 1, 2, 3 and 7dpa stages against control non-regenerating tissue. Interleukin, SLC, PRMT, HOX, neurotransmitter and several novel genes were found to be associated with regeneration for its differential regulation during the mechanism. Based on the network and pathway analysis the differentially regulated genes and proteins were found allied with activation of cell proliferation, cell viability, cell survival & cell movement and inactivation of organismal death, morbidity, necrosis, death of embryo & cell death. Network pathways such as Cancer & development disorder, Cell signaling molecular transport, organismal injury & abnormalities and Cellular development, growth & proliferation were found most significantly associated with the zebrafish caudal fin regeneration mechanism. This study has mapped a detailed insight of the genes/proteins expression associated with the epimorphic regeneration more profoundly.

developmental biology↗

bioRxiv2018

Functional Role of Annexins in Zebrafish Caudal Fin Regeneration: A Gene Knockdown Approach in Regenerating Tissue.

Regeneration is an adaptive phenomenon with wide biological implications spread heterogeneously in almost all the organism including human beings. The ability of regeneration varies from species to species for its impediment. Epimorphic regeneration of zebrafish caudal fin tissue is most widely studied regeneration mechanism for its discrete and rapid regenerative capability. Several genes/proteins were found to be associated with zebrafish caudal fin tissue regeneration. Here, we have evaluated the functional role of Annexin 2a and 2b genes in adult zebrafish caudal fin tissue undergoing regeneration using a novel CRSISPR-Cas9 gene knock down approach. Knock down of both the genes individually elicited in decelerated regeneration and down regulation of target genes and its partner genes/proteins such as ANXA1a, ANXA5b and ANXA13. This study validates a novel gene targeting approach and the possible role of annexin in regeneration mechanism.

developmental biology↗