Programme d'impulsion

ThermoMito

Role of TRPV1 variants in mitochondrial thermogenesis and susceptibility to heat strokes

| Overview

Duration: 24 months
Budget: 119 600 euros

Scientific coordination :
Guy Lenaers, Mitolab Team, Unité MitoVasc, U1083 Inserm

| Context

Humans are homeothermic species that balance thermogenesis and thermolysis to adapt their body temperature to changing environmental conditions. Thermogenesis relies on mitochondria to act as sub-cellular radiators potentially reaching 50°C to ensure a stable 37°C body normo-temperature. Whether mitochondria need a thermostat to modulate its maximal temperature to prevent deleterious over-heating and maintain a cellular temperature homeostasis is not known. 

We propose a newly discovered isoform of the calcium channel TRPV1 located in mitochondria (mitoTRPV1), present only in mammals, to be this missing link.  Our data (being patented) demonstrate that mitoTRPV1 localizes to mitochondria, where its activation lowers mitochondrial temperature by 10°C without impacting cellular respiration.

ThermoMito challenges consist in exploring how mitoTRPV1 acts as a mitochondrial thermostat regulating thermogenesis, how TRPV1 specific variants modulate mitoTRPV1 functions and have contributed to the adaptation of human populations to their actual climate niches, and how other know pathogenic TRPV1 variants responsible for hyperthermia are affecting the sensitivity of this mitochondrial thermostat.

| Aims

ThermoMito proposal will address 3 central specific objectives:

  • Understand at the molecular, mitochondrial, and cellular levels, how mitoTRPV1 senses and controls mitochondrial temperature
  • Identify among the 1500 known TRPV1 variants, the ones that contributed to the adaptation of human populations to their actual climate niches, considering an equator-pole latitudinal gradient
  • Characterize the impacts of these adaptative TRPV1 variants and the ones responsible for pathologic hyperthermia on mitochondrial temperature and physiology

| Perspectives

Altogether, ThermoMito implementation will provide fundamental knowledge on the first key-player linking mitochondrial thermo-regulation to homeothermy, genomic biomarkers to stratify human populations’ susceptibility to hyperthermia, and a possible target for drug design aiming at lowering body temperature in case of high thermal stress, with the utmost opportunity to ensure a better resilience, adaptation and wellbeing management of humans facing heat strokes and the context of global warming, as recommended by WHO, EU and IPCC strategies.