Identification of a human mitochondrial isoform of TRPV1: a thermostat regulating mitochondrial maximal temperature?

Mitochondria are well known to produce ATP for cell energy requirements and thermogenesis simultaneously by the respiratory chain, with a potential optimum temperature of 50 °C, while deleterious overheating should be prevented by a yet unknown system. Here, we report the identification of a human Transient Receptor Potential Vanilloid 1 (mitoTRPV1) alternative isoform located in the mitochondrial inner membrane, which acts as a thermostat regulating mitochondrial maximal temperature. The ubiquitously expressed mitoTRPV1 open reading frame overlaps TRPV1 exons 1 and 2 and intron 2 in a + 1 frame, encoding for an effective 150 amino-acid N-terminal mitochondrial targeting sequence (MTS) conserved amongst mammalian species, followed by the 687 amino acids of the TRPV1 C-terminal sequence. Pharmacological activation of mitoTRPV1 induces a low cytoplasmic Ca²⁺ increase and mitochondrial cooling without modification of mitochondrial respiration and ATP production. We conclude that, in our experimental conditions, mitoTRPV1 acts as a thermostat to promote mitochondrial thermolysis without impairing respiration and ATP production. They point to the potential implication of mitoTRPV1 in human diseases related to temperature dysregulation, and should be further studied in physiological conditions in cellular and animal models expressing mitoTRPV1 endogenously.