Involvement of mitochondria in the pathophysiology of the exertional heat stroke. Towards the identification of novel biomarkers. – TEMPOMITO

Exertional Heat Stroke (EHS) is a syndrome related to increased body temperature, often observed during endurance sports and in serving military personnel. Poorly managed, it can lead to a comatose state and death of the patient. At present, it is recognized that there is significant individual variability in physiological tolerance to heat, the part of which is still debated. In addition, no reliable biological marker is available to anticipate the risk of developing an EHS, to consider its medium-term consequences and to predict the likelihood of recurrence.
It is therefore essential to better characterize the link between biological factors and physiological responses. This requires conducting cross-sectional studies to advance the biological substrate of thermogenesis and the functional impact of specific biological and genetic profiles on heat production that could contribute to individual heat tolerance and the risk of triggering an EHS.
A key element of this issue lies in the mitochondria, a cellular organelle which main function consists in providing useful energy to the cell, i.e. Adenosine Tri-Phosphate (ATP), which synthesis is accompanied by the thermogenesis responsible for homeothermy in mammals. Paradoxically, the involvement of this organelle, and in particular its metabolism, its genome, its role in calcium homeostasis and its temperature have never been taken into account in the pathophysiology of the EHS.
The TEMPOMITO project aims to study the implication of mitochondrial temperature dysregulation, which is now known to be physiologically close to 50°C, as the basis of the EHS, and to identify relevant genetic and metabolic biomarkers of predisposition to EHS.
The TEMPOMITO project brings together 4 partners with complementary expertise, whose past and present works represent a unique opportunity to address this research, because of their contribution to the identification of the first variants of RyR1 and TRPV1, the only two genes currently known predisposing to EHS, the development of a technology to measure mitochondrial temperature in cells, the development of the concept of medical metabolomics, and the recruitment of the largest national cohort of defence personnel who have undergone an EHS.
Three lines of research will be conducted:
1. an analysis of the genetic determinants of EHS predisposition from a collection of DNA from a cohort of military personnel with a history of EHS. Particular focus will be placed on the RyR1 and TRPV1 genes, and on the mitochondrial haplogroup, all three known for their involvement in the control of thermogenesis,
2. the determination of a metabolomic signature in humans and rats exposed to a calibrated exercise in a controlled warm thermal environment, by the analysis by mass spectrometry of their plasma collected before during and after this stress,
3. the characterization of mitochondrial physiology (respiration, temperature, and calcium fluxes) within cells expressing wild-type and mutated alleles of RyR1 and TRPV1, and the evaluation of the effects of agonists and antagonists of these ion channels on these mitochondrial parameters.
Together, the expected results will help clarifying the molecular parameters involved in the EHS pathophysiology, defining biomarkers with the prospect of better predicting and thus preventing EHS, and laying the theoretical basis for future pharmacological management of EHS. Outcomes will concern hot OPEX, high-thermal endurance sport challenges, and in a close future the entire world population, which will be exposed to global warming.