Mitochondria have long been recognized for the production of energy within cells. But there is more than one type of energy. In a recent review, Jacobs et al. (2024)1 described the results of their studies and that of others that show how mitochondria produce heat as well as chemical energy. Like many motors, mitochondria produce heat at the same time as performing ‘work’. Furthermore, they note that the heat produced by mitochondria might have been important in the evolution of eukaryotes and warm-blooded animals (e.g., birds, mammals).

Jacobs et al. used heat-sensitive dyes and fluorescent proteins to measure the temperature of mitochondria. They found that the temperature of the mitochondria was about 15°C higher than the environment.

They speculate that the heat energy had profound effects on life on Earth. First, eukaryotes resulted from an endosymbiotic relationship between a bacterium and another prokaryotic organism. The bacterium evolved into a mitochondrion. For some time, the assumption has been that the proto-mitochondrion provided additional chemical energy as ATP. However, Jacobs et al. point out that the most likely partner was an archaean that lived near a hydrothermal vent, as proposed originally by Dunn (2017)2. By entering into a partnership, the proto-mitochondrion provided heat that allowed the hybrid organism to move away from the warm waters of the hydrothermal vent. The most compelling aspect is that the transfer of heat does not require the evolution of additional mechanisms for transfer that ATP does. Second, the heat from mitochondria might have allowed warm-blooded animals to evolve.

While still just a hypothesis, the involvement of heat in evolution is an intriguing possibility that suggests lots of additional experiments.

1Jacobs HT, Rustin P, Bénit P, Davidi D, Terzioglu M (2024) Mitochondria: Great balls of fire. The FEBS Journal 291: 5327-5341. https://doi.org/10.1111/febs.17316

2Dunn CD (2017) Some liked it hot: A hypothesis regarding establishment of the proto-mitochondrial endosymbiont during eukaryogenesis. Journal of Molecular Evolution 85: 99-106. https://doi.org/10.1007/s00239-017-9809-5

 

We appreciate the willingness of lead author Howy Jacobs of Tampere University, Finland, to answer some questions about the significance of heat from mitochondria.For some time, biologists had assumed that energy was the main bartering chip provided by mitochondria to the new eukaryotes. Could heat be an equal driver, as Dunn suggests?

Well, heat IS a form of energy! What we are proposing is that heat produced by mitochondria (or by aerobic bacteria) is a crucial factor in eukaryote biology, that has been largely overlooked. We propose that it has a crucial role not only in evolution but also in many aspects of cell biology, metabolism, immunity, physiology and disease. Dunn’s idea is, of course, really only speculation at this point, but is now supported by the evidence that the ancient host cell that engulfed the mitochondrial ancestor was a moderate thermophile. Note also that it is not completely accurate to regard heat and ATP as alternative forms of energy produced by mitochondria: the energy conserved in the form of ATP and exported to the rest of the cell can also be converted partly or even entirely into heat. For example, the pumping action of the heart depends heavily on mitochondrial ATP production, but only a part of the stored energy drives the contractile action of the heart muscle, the rest being converted to heat which is then carried away in the bloodstream to maintain body temperature. Note that ATP may not be the only ‘energy-rich’ molecule produced by mitochondria that could be considered as a heat store.

Are you planning to measure the temperature of chloroplasts?

We are not planning to do this ourselves but at some point someone needs to do it. But it is going to require a different technology than the ones we have been using, which are based on fluorescent dyes and proteins. The green pigments naturally present in the photosynthetic system would just obliterate any signal. But the existing technologies should suffice to measure the intracellular temperature of aerobic bacteria and also to test our idea that the bacterial cell wall functions as an insulating layer.

Mitochondrial heating seems to open an entirely new way of looking at biology. There are so many manifestations that seem to be covered by it.

I am sure that the topics covered in our short review are far from exhaustive. Here are a few more than could be considered (but undoubtedly there are many others). We have suggested that ‘heat delivery’ could be a mechanism for killing pathogens or infected cells. But maybe it also plays a wider role in programmed cell death, which is a major process in animal and plant development, tumour suppression and stress management. Heat (or its absence) may also play a pivotal role in many diseases, notably neurodegeneration, where the accumulation of protein aggregates is an obligatory step in pathology. And if mitochondria do contain a store of heat-buffering molecules as suggested above, they might also function in some contexts to absorb excess heat coming from the environment.

What is the relationship between mitochondrial heating in brown adipose tissue and other tissues? Are there simply more mitochondria in brown adipose?

Although intensively studied, there are still outstanding questions as to how brown adipocyte mitochondria are ‘repurposed’ to deliver heat rather than ATP. One major mechanism is clearly the expression and activation of the uncoupler protein UCP1, which provides a proton channel in the inner mitochondrial membrane, thus dissipating the proton gradient that is normally driving ATP synthesis, instead releasing all the energy of substrate oxidation as heat. But the normal functioning of the respiratory chain in other tissues lacking UCP1 also generates heat, since only about half of the energy yield from biological oxidation is conserved by proton pumping against the gradient. The rest is converted to heat.

Do you have any speculation about the control systems for this heat?

Our FEBS Journal paper makes some suggestions as to the possible nature of heat sensors inside mitochondria (and the rest of the cell). But for now this is purely in the realm of speculation. The narrow temperature range tolerated by mammalian cells suggests that mitochondrial heat output must be finely regulated, almost certainly by multiple, i.e. redundant systems operating in parallel, as for almost all of the important processes in biology. Such redundancy invariably makes it hard to identify the relevant machinery using the standard tools of genetics.

Is it possible to determine the efficiency of mitochondria?

I don’t much care for this term, since it implies that heat production is somehow a wasteful by-product of mitochondrial metabolism. Thermodynamically it is appropriate, but biologically not! Rather I think we should be thinking about the overall energy transactions taking place, that result in the generation (or absorption) of heat, the production of heat- storage molecules (thus far not identified) and of ‘dual-use’ molecules, predominantly ATP, as a store of useful energy to drive biochemical, mechanical or electrical processes, as well as heat production. Yes, we can start to measure all these, and theoretical considerations can help, but to do this fully we need to identify all the cell’s heat storage systems and derive a more accurate picture of heat flow within the cell, including the temperature gradients within and between cellular compartments – not just mitochondria. Recent findings that mitochondria even within a single cell type can be functionally diverse further complicate the picture. So we are a long way from the end goal of comprehensively profiling energy transactions inside cells, let alone tissues and organs.

How did you get interested in mitochondria?

As so often in science, by studying something else and stumbling into mitochondria by accident. Details on request if you are really interested!