Biology subjects

Magistretti, P. J.

Publications and source records attributed to Magistretti, P. J..

6 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↗

bioRxiv2023

Proteome profiling of nasopharynx reveals pathophysiological signature of COVID-19 disease severity

An aberrant innate immune system caused by the beta coronavirus SARS-CoV-2 is a characteristic manifestation of severe coronavirus disease 2019 (COVID-19). Here, we performed proteome profiling of nasopharyngeal (NP) swabs from 273 hospitalized patients with mild and severe COVID-19 symptoms, including non-survivors. We identified depletion in STAT1-mediated type I interferon response, retinol metabolism and NRF2 antioxidant system that are associated with disease severity in our patient demography. We found that the dysregulation of glucocorticoid signaling and renin-angiotensin-aldosterone system (RAAS) contribute to the pathophysiology of COVID-19 fatality. Hyperactivation of host innate immune system was observed in severe patients, marked by elevated proteins involved in neutrophil degranulation and platelet aggregation. Our study using high-throughput proteomics on the nasopharynx of COVID-19 patients provides additional evidence on the SARS-CoV-2-induced pathophysiological signatures of disease severity and fatality.

immunology↗

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↗

bioRxiv2020

Spike-frequency adaptation is modulated by interacting currents in an Hodgkin-Huxley-type model: Role of the Na,K-ATPase

Spike-frequency adaptation is a prominent feature of spiking neurons. Using a Hodgkin-Huxley-type model, we studied adaptation originating from the Na,K-ATPase electrogenic pump and its evolution in presence of a medium-duration calcium-dependent potassium channel. We found that the Na,K-ATPase induces spike-frequency adaptation with a time constant of up to a few seconds and interacts with the calcium-dependent potassium current through the output frequency, yielding a very typical pattern of instantaneous frequencies. Because channels responsible for spike-frequency adaptation can interact with each other, our results suggest that their meaningful time courses and parameters can be difficult to measure experimentally. To circumvent this problem, we developed a simple phenomenological model that captures the interaction between currents and allows the direct evaluation of the underlying biophysical parameters directly from the frequency vs. current curves. Finally, we found that for weak stimulations, the pump induces phasic spiking and linearly converts the stimulus amplitude in a finite number of spikes acting like an inhibitory spike-counter. Our results point to the importance of considering interacting currents involved in spike-frequency adaptation collectively rather than as isolated elements and underscore the importance of sodium as a messenger for long-term signal integration in neurons. Within this context, we propose that the Na,K-ATPase plays an important role and show how to recover relevant biological parameters from adapting channels using simple electrophysiological measurements.

neuroscience↗

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↗