The hot mitochondrion paradox: reconciling theory and experiment

Abstract

Experiments by Chrétien and coworkers suggest that mitochondria are 10°C hotter than their surroundings. Steady-state theoretical estimates place this difference at a maximum of 10 −5 °C. This millionfold disagreement may be called the 'hot mitochondrion paradox'. It is suggested that every proton translocated via ATP synthase sparks a picosecond temperature-difference spike of the order of magnitude measured by Chrétien et al. Time averaging of these spikes recovers the theoretical value. Further, a temporal and spatial superposition of the fluorescence intensity of a very large number of molecular thermometer molecules in the sample can give the appearance of a steady signal. The inner mitochondrial membrane appears to be flanked by temperature differences fluctuating in time and along the membrane's surface, with 'hot' and 'cold' spots as ultrashort temperature spikes. An apparent millionfold disagreement of theory and experiment HighlightsExperiments suggest a 10°C temperature difference between the mitochondrion and its surroundings in a millionfold disagreement with steadystate theoretical estimates.Both experiment and theory appear to be solidly founded, so we have a paradox.ATP synthase is modelled as a modified Feynman ratchet engine coupling two separate heat baths.The paradox is resolved by understanding that the appearance of the steady measurement of a temperature difference is the result of continually recording sharp, picosecond spikes of temperature difference the time averaging of which leads to the theoretical value.

The multiple facets of mitochondrial regulations controlling cellular thermogenesis

“…A further reconciliation between theory and practice was suggested by the observation of picosecond temperaturedifference spikes, compatible with the 50°C temperature of mitochondria. Indeed, when these picosecond spikes were averaged over time, a 10°C difference of temperature was observed between mitochondria and cytoplasm, consistent with the maintenance of a chronic steady-state temperature gradient, rather than acute picosecond heat spikes (Fahimi et Matta 2021). Moreover, the concept of transient heat release was also observed experimentally, as a transient heat shock of ≈7.5°C was observed during proton uncoupling using the chemical uncoupler BAM15 (Rajagopal et al 2019).…”

ATP synthase: a moonlighting enzyme with unprecedented functions

“…Furthermore, recent examination of the heat conduction around ATP synthase uncovers the role of this enzyme in generating temporary short-lived (picoseconds) temperature gradient spikes with every proton translocation. 51 This view of ATP synthase supports the heat engine character ascribed to this enzyme by Muller. 52,53 Temporal superposition of these spikes in nanothermometry experiments of Chrétien et al can give rise to substantial temperature difference between mitochondria and their surroundings.…”

Succinate Dehydrogenase, Succinate, and Superoxides: A Genetic, Epigenetic, Metabolic, Environmental Explosive Crossroad

“…Interestingly, the gap between the high temperature values locally measured in mitochondria and the theoretical predictions is gradually fulfilled by growing evidence of unexpected intracellular thermal conductivity variations [71]. This might fit with the idea that transient temperature spikes occur in order to allow for significant heat differential between mitochondria, or part of it, and the surrounding cytosol under specific conditions [72].…”