Biology subjects

Fiumelli, H.

Publications and source records attributed to Fiumelli, H..

4 recordsLinked to original sources

bioRxiv2025

Lactate promotes longevity through redox-driven lipid remodeling in Caenorhabditis elegans.

Lactate has emerged as a key metabolite involved in multiple physiological processes, including memory formation, immune response regulation, and muscle biogenesis. However, its role in aging and cellular protection remains unclear. Here, we show that lactate promotes longevity in C. elegans through a mechanism that requires early-life intervention, indicating a hormetic priming effect. This pro-longevity action depends on its metabolic conversion via LDH-1 and NADH, which drives redox-dependent metabolic reprogramming. Multi-omics approaches revealed that lactate induces early-stage metabolic adaptations, with a strong modulation of lipid metabolism, followed by late-life transcriptional remodeling. These shifts are characterized by enhanced stress response pathways and suppression of energy- associated metabolic processes. Our genetic screening identified sir-2.1/SIRT1 and rict- 1/RICTOR as essential for lactate-mediated lifespan extension. Our findings establish lactate as a pro-longevity metabolite that couples redox signaling with lipid remodeling and nutrient- sensing pathways. This work advances our understanding of lactates dual role as a metabolic intermediary and geroprotector signaling molecule, offering insights into therapeutic strategies for age-related metabolic disorders.

physiology↗

bioRxiv2024

Lactate potentiates NMDA receptor currents via an intracellular redox mechanism targeting cysteines in the C-terminal domain of GluN2B subunits: implications for synaptic plasticity

SummaryThrough the Astrocyte Neuron Lactate Shuttle, astrocyte-derived lactate fuels the high-energy demands of neurons and acts as a signaling molecule, promoting synaptic plasticity and memory consolidation. Lactate regulates neuronal excitability and modulates the expression of genes related to synaptic plasticity and neuroprotection, but the molecular mode for these signaling actions is uncertain. Using patch-clamp recordings in cultured cortical neurons, we found that lactate enhances both the amplitude and the inactivation time constant of NMDA receptor currents (INMDAR) evoked by brief applications of glutamate and glycine. Not reproduced by HCAR1 agonists, this modulation depends on monocarboxylate transporters and lactate dehydrogenase, indicating the requirement for lactate entry and metabolic conversion into pyruvate and NADH formation within neurons. Disruption of intracellular calcium dynamics or inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a NMDAR-associated kinase linking Ca2+ signal to long-term potentiation (LTP), significantly diminishes the effects of lactate on INMDAR. We identified two redox-sensitive cysteine- containing sequences in the intrinsically disordered intracellular C-terminal domain of the GluN2B subunit that play a role in the potentiation of NMDAR by lactate. In a compelling set of experiments using HEK cells, we observed that the presence of functional CaMKII and GluN2B-containing NMDARs is necessary for the lactate-enhancing effects. Mutations in GluN2B that prevent CaMKII binding or redox regulation via cysteines abrogate the modulatory action of lactate. Immunoprecipitation experiments in neurons attest that lactate increases the association between CaMKII and GluN2B. This interaction is crucial for the potentiation of INMDAR amplitude by lactate. Proximity ligation assays between GluN2B and the postsynaptic density marker PSD-95 revealed that lactate induced an accumulation of GluN2B in dendritic spines, an effect that was prevented by a CaMKII peptide inhibitor. These results highlight a mechanistic pathway whereby lactate boosts NMDAR function through intracellular metabolic conversion and redox-sensitive interactions requiring CaMKII, establishing a link between astrocyte metabolism and synaptic modulation in neurons.

neuroscience↗

bioRxiv2022

Photo-electrochemical Stimulation of Neurons With Organic Donor-Acceptor Heterojunctions

Recent advancements in light-responsive materials enabled the development of devices to artificially activate tissue with light, and show great potential for use in different types of therapy. Photo-stimulation based on organic semiconductors has recently attracted interest due to their unique set of properties such as biocompatibility, better mechanical match with human tissue, and strong absorption of light in the visible spectrum. Here we show the development of solution processed organic heterojunctions that are able to control the activity of primary neurons in vitro with light. The p-type polymer semiconductor PDCBT and the n-type polymer semiconductor ITIC (also known as non-fullerene acceptor) are simply spin coated on glass substrates forming a bilayer p-n junction with high photo-sensitivity in aqueous electrolytes. Photo-electrochemical measurements reveal that high photo-voltage and photo-current is produced, as a result of a charge transfer between the polymers and oxygen in the electrolyte. The biocompatibility of the proposed materials is addressed with live/dead assays on both primary mouse cortical neurons and human cell lines that are cultured on their surface. We have found that light of low intensity (i.e. 40 mW/cm2) is absorbed, and converted into a cue that triggers action potential on primary cortical neurons directly cultured on glass/PDCBT/ITIC interfaces as proven by patch clamp measurements. The activation of neurons is most likely due to photochemical reactions at the polymer/electrolyte interface that result in hydrogen peroxide, which might lead to modulation of specific ion channels on neurons membrane. Photo-thermal effects are excluded with controlled patch clamp measurements on neurons cultured on plain glass and on photoresist thin films. The profound advantages of low intensity light stimulation, simplified fabrication, and wireless operation pave the way for the integration of these interfaces in multiplex bioelectronic devices for the development of novel light therapy concepts and powerful neuroscience research tools.

bioengineering↗

bioRxiv2019

Lactate and pyruvate promote cellular stress resistance and longevity through ROS signaling.

L-lactate, for long considered a glycolytic end-product, is now recognized as an important energy substrate. Moreover, it appears that its role is not limited to energy production but also as a signal for neuroprotection and synaptic plasticity. Using a model of neuroblastoma cells and the nematode C. elegans we investigated the cellular mechanisms underlying this protective role of L-lactate. We found that L-lactate promotes a mild Reactive Oxygen Species (ROS) induction that translates into activation of antioxidant defenses and pro-survival pathways such as PI3K/AKT and Endoplasmic Reticulum (ER) chaperones. This hormetic mechanism provides protection against oxidative stress in both cells and nematodes. Furthermore, a mild ROS induction by lactate also promotes longevity in C. elegans.

cell biology↗