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Lantz, C.

Publications and source records attributed to Lantz, C..

6 recordsLinked to original sources
bioRxiv2025

LncRNA H19 Upregulation Links Hypoplastic Left Heart Syndrome to Impaired PINK1/Parkin-Mediated Mitophagy and Ischemic Vulnerability

BACKGROUNDThe myocardium in hypoplastic left heart syndrome (HLHS) exhibits immature metabolic programming, impaired mitochondrial quality control, and heightened susceptibility to ischemic and hypoxic injury during palliative surgery. The long non-coding RNA H19 suppresses translation of PTEN-induced putative kinase 1 (PINK1) mRNA and modulates mitochondrial quality control and ischemia/reperfusion injury (IRI) in adult hearts. Whether--and how--H19 regulates mitophagy and IRI in HLHS or in immature animals remains unknown. METHODSWe investigated H19 regulation and its role in mitophagy and ischemia/reperfusion or hypoxia/reoxygenation injury in myocardial tissue from HLHS patients, HLHS-specific induced pluripotent stem cell-derived cardiomyocytes (HLHS-iPSC-CMs), and immature rat hearts. Mechanistic interactions among H19, PINK1/Parkin signaling, and mitophagosome formation were assessed using loss-of-function approaches. RESULTSHLHS myocardium exhibited markedly elevated H19 expression, accompanied by reduced PINK1 and Parkin protein abundance and diminished mitophagosome formation. Similar findings were observed in HLHS-iPSC-CMs exposed to hypoxia/reoxygenation and in immature rat hearts subjected to myocardial IRI. H19 knockdown in HLHS-iPSC-CMs attenuated hypoxia/reoxygenation-induced lactate dehydrogenase release and restored PINK1 and Parkin protein levels. In immature rats, myocardial H19 silencing reduced infarct size, enhanced mitochondrial PINK1 and Parkin expression, and improved post-reperfusion cardiac function for up to 28 days. Conversely, knockdown of PINK1 or Parkin reduced mitophagosome formation and exacerbated functional deterioration during IRI. CONCLUSIONSH19 upregulation impairs PINK1/Parkin-dependent mitophagy and increases susceptibility to ischemic and hypoxic injury in HLHS and the immature heart. These findings identify H19 as a key regulator of mitochondrial quality control and a potential therapeutic target for mitigating IRI in early-life cardiac disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/694773v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@193defdorg.highwire.dtl.DTLVardef@114ce7forg.highwire.dtl.DTLVardef@1010d05org.highwire.dtl.DTLVardef@1fdeac1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIThe myocardium in hypoplastic left heart syndrome (HLHS) exhibits immature metabolic programming, abnormal coronary perfusion, and impaired mitochondrial quality control, rendering it highly susceptible to ischemic and hypoxic injury. C_LIO_LIBoth structural limitations and intrinsic mitochondrial dysfunction contribute to the reduced ischemic tolerance of the HLHS heart, particularly during surgical and hemodynamic stress. C_LIO_LIThe long noncoding RNA H19 regulates mitochondrial quality control and modulates myocardial ischemia/reperfusion injury (IRI) in adult hearts. C_LIO_LIH19 inhibits the binding of the translation initiation factor eIF4A2 to PTEN-induced putative kinase 1 (PINK1) mRNA, thereby suppressing PINK1 protein synthesis and influencing PINK1-dependent mitophagy in adult mice. C_LI What New Information Does This Article Contribute?O_LIThis study identifies robust upregulation of H19 in HLHS myocardium, HLHS-specific induced pluripotent stem cell-derived cardiomyocytes (HLHS-iPSC-CMs) exposed to hypoxia/reoxygenation, and in immature rats subjected to myocardial IRI. C_LIO_LIElevated H19 is associated with suppressed PINK1/Parkin-dependent mitophagy, exacerbated IRI, and adverse post-injury remodeling. C_LIO_LIKnockdown of H19 restores mitochondrial PINK1 and Parkin protein levels, enhances mitophagy, reduces infarct size, and improves long-term recovery of cardiac function--demonstrating a previously unrecognized pathogenic role for H19 in the immature heart under stress. C_LIO_LIKnockdown of PINK1 or Parkin decreases mitophagosomes and exacerbates myocardial IRI in immature rats. C_LI

genomics↗
bioRxiv2025

Microglial metabolic reprogramming drives cognitive decline in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a rapidly growing public health concern and an emerging contributor to dementia, yet the mechanisms linking cardiometabolic dysfunction to neurodegeneration remain poorly understood. Here, we demonstrate that HFpEF drives a sustained neuroinflammatory state through microglial metabolic reprogramming. Using a clinically relevant murine model of HFpEF, we identified robust induction of HIF-1 signaling in microglia via integrated transcriptomics and metabolomics, coupled with increased glycolytic metabolism revealed by extracellular flux analysis. Conditional deletion of Hif1a in microglia during HFpEF attenuated neuroinflammation, preserved white matter integrity, and rescued cognitive performance. We further identify Sema4D as a HIF-1-dependent, microglia-derived effector linking metabolic stress to white matter injury. These findings establish a mechanistic bridge between cardiovascular disease and cognitive dysfunction and reveal microglial HIF-1 signaling as a tractable therapeutic strategy for preventing cognitive decline in cardiometabolic disease.

immunology↗
bioRxiv2025

The NIH BRAIN Initiative's Experiment in Team Research

Withdrawal StatementThe authors have withdrawn this manuscript because this manuscript has been merged with another preprint (BIORXIV/2025/635684). Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The merged preprint can be found at doi:10.1101/2025.01.30.635684

neuroscience↗
bioRxiv2025

Allosteric Modulation of Pathological Ataxin-3 Aggregation: A Path to Spinocerebellar Ataxia Type-3 Therapies

Spinocerebellar ataxia type 3 (SCA3) is a rare inherited neurodegenerative disease caused by the expansion of a polyglutamine repeat in the protease ataxin-3 (Atx3). Despite extensive knowledge of the downstream pathophysiology, no disease-modifying therapies are currently available to halt disease progression. The accumulation of protein inclusions enriched in the polyQ-expanded Atx3 in neurons suggests that inhibiting its self-assembly may yield targeted therapeutic approaches. Here it is shown that a supramolecular tweezer, CLR01, binds to a lysine residue on a positively charged surface patch of the Atx3 catalytic Josephin domain. At this site, the binding of CLR01 decreases the conformational fluctuations of the distal flexible hairpin. This results in reduced exposure of the nearby aggregation-prone region, which overlaps with the substrate ubiquitin binding site and primes Atx3 self-assembly, ultimately delaying Atx3 amyloid fibril formation and reducing the secondary nucleation rate, a process linked to fibril proliferation and toxicity. These effects translate into the reversal of synapse loss in a SCA3 cultured cortical neuron model, an improved locomotor function in a C. elegans SCA3 model, and a delay in disease onset, accompanied by reduced severity of motor symptoms in a SCA3 mouse model. This study provides critical insights into Atx3 self-assembly, revealing a novel allosteric site for designing CLR01-inspired therapies targeting pathological aggregation pathways while sparing essential functional sites. These findings emphasize that targeting allosteric sites in amyloid-forming proteins may offer unique opportunities to develop safe therapeutic strategies for various protein misfolding disorders.

biophysics↗
bioRxiv2024

HIF-1alpha is Required to Differentiate the Neonatal Macrophage Secretome from Adults

The immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages polarized to an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent on hypoxia inducible transcription factor-1 (HIF-1). In contrast, adult macrophages adopted a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age and HIF-1 dependent macrophage programs that may be targeted to calibrate the innate immune response during stress and inflammation.

immunology↗