Biology subjects

Mattei, C.

Publications and source records attributed to Mattei, C..

3 recordsLinked to original sources

bioRxiv2024

A human mitochondrial isoform of TRPV1 regulates intracellular Ca2+ simultaneously with mitochondrial thermolysis

Mitochondria are the cornerstones of cellular and body thermogenesis, with an inner temperature possibly reaching 50{degrees}C. Here, we report the identification of a human Transient Receptor Potential Vanilloid 1 alternative isoform located in mitochondria. This isoform, which we have termed mitoTRPV1, acts as a thermostat to restrict the mitochondrial temperature. The mitoTRPV1 open reading frame overlaps TRPV1 exons 1 and 2 and intron 2 in a +1 frame, encoding for a predicted 150 amino-acid N-terminal mitochondrial targeting sequence (MTS) conserved amongst mammalian species, followed by the 687 amino acids of TRPV1 C-terminal. This ORF is ubiquitously expressed in most human organs, underscoring its broad relevance. The deduced MTS, conserved among mammalian species, effectively addresses this TRPV1 isoform to the mitochondrial inner membrane. Our experiments, using heterologous wild-type and mutated mitoTRPV1 expression, combined with Ca2+ imaging, mitochondrial temperature and oxygraphy measurements, disclosed that mitoTRPV1 activation induces Ca2+ efflux and mitochondrial cooling, without modification of mitochondrial respiration and ATP production. Notably, the loss of function mitoTRPV1-G684V isoform, responsible for exertional heat stroke predisposition in humans, abolished mitochondrial Ca2+ efflux and cooling. These findings reveal a new thermolysis function for TRPV1 in preventing mitochondrial overwarming while not affecting the OXPHOS efficiency. They also highlight the potential implications of mitoTRPV1 in human diseases related to temperature dysregulation.

cell biology↗

bioRxiv2024

Emerging neurodevelopmental mechanisms in patient induced pluripotent stem cells-derived spheroids modelling SCN1A Dravet Syndrome

SCN1A encodes Na1.1, a voltage-gated sodium channel preferentially expressed in GABAergic interneurons, and it is the major cause of Dravet Syndrome (DS), a rare condition of developmental and epileptic encephalopathy (DEE). Among over 1000 DS mutations reported to date, almost all cause SCN1A loss-of function (LoF). A reduction in NaV1.1 function in inhibitory neurons would subsequently cause an over-excitation of glutamatergic neurons resulting in seizures, which are exacerbated by the use of sodium channel blocking common anti-seizure medications (ASM). In this study we generated and assessed 3D spheroids enriched with GABAergic neurons from SCN1A DS patient to establish a 3D human-derived DS model. To investigate developmental disruptions in DS pathophysiology we profiled the transcriptome of patient-derived spheroids and subsequently, tested the capability of this 3D in vitro model to reveal the cellular mechanisms of DS and predict drug response. In summary, our patient iPSC-derived neuronal model of SCN1A DS revealed a profound dysregulation of developmental processes which correlated with functional disruption in GABAergic neurons and predicted response to fenfluramine, an ASM increasingly used for the treatment of DS.

neuroscience↗

bioRxiv2023

Distinctive in vitro phenotypes in iPSC-derived neurons from patients with gain- and loss-of-function SCN2A developmental and epileptic encephalopathy

SCN2A encodes NaV1.2, an excitatory neuron voltage-gated sodium channel and major monogenic cause of neurodevelopmental disorders, including developmental and epileptic encephalopathies (DEE) and autism. Clinical presentation and pharmocosensitivity vary with nature of SCN2A variant dysfunction with gain-of-function (GoF) cases presenting with pre- or peri-natal seizures and loss-of-function (LoF) patients typically having infantile spasms after 6 months of age. Here, we established and assessed patient induced pluripotent stem cell (iPSC) - derived neuronal models for two recurrent SCN2A DEE variants with GoF R1882Q and LoF R853Q associated with early- and late-onset DEE, respectively. Patient-derived iPSC lines were differentiated using a Neurogenin-2 overexpression yielding populations of cortical-like glutamatergic neurons. Electrophysiological and transcriptomic profiles were assessed after 2-4 weeks in culture. Increased neuronal activity at both cellular and network level was observed for R1882Q iPSC-derived neurons at three weeks of differentiation. In contrast, R853Q neurons showed only subtle changes in excitability after four weeks in vitro. In alignment with the reported efficacy in some GoF SCN2A patients, phenytoin (sodium channel blocker) reduced excitability of neurons to the control levels in R1882Q neuronal cultures. Transcriptomic alterations in neurons were detected for each variant and convergent pathways pointed at the shared mechanisms underlying SCN2A DEE.

neuroscience↗