2021 December 14

The histone MacroH2A has been controlling the energy balance within animal cells since the dawn of the lineage

Researchers at the Josep Carreras Leukaemia Research Institute find that the macro domain of histone variant macroH2A is one of the regulators of the NAD+ balance between the nuclear compartment and the mitochondria, and has been since the time of the pre-metazoan protists.

Every high schooler keen on biology knows that, inside a cell, energy is transported in the form of ATP, a highly energetic molecule. It is synthesized mostly in the mitochondria, on the respiratory chain, largely by using the proton carrier NAD+. Since the amount of both ATP and NAD+ are finite into the cell, its consumption must be carefully regulated to ensure there is enough energy to fulfill the vital functions of the organism.

Two of the most energy intense compartments in a cell are the mitochondria and the nucleus. Balancing the energy flow between those is vital to keep the basic homeostasis under control and now, researchers from the Buschbeck lab report that one of the proteins involved in this balance seems to be, as surprising as it sounds, a histone. More precisely, the histone variant macroH2A.

In a paper recently published at Nature Structural & Molecular Biology, authored by Iva Guberovic and supervised by Marcus Buschbeck, researchers found out that macroH2A can interact with PARP1, one of the main consumers of NAD+ in the nucleus, through its macro domain, inhibiting its action and lowering the total energy consumption of the nuclear compartment.

Furthermore, low energy consumption in the nucleus was associated to non-proliferative states, such as the spore-like form of the protist Capsaspora, used to resist hash environmental conditions and allowing it to survive.

Survival is paramount for living organisms and this could explain why this balancing activity of macroH2A has been conserved throughout the evolutionary history of the animal kingdom. Guberovic and colleagues’ analysis concludes its origin and diversification occurred during the protist to invertebrate transition, one thousand million years ago, and has been changing since then until becoming a part of the subtle energy regulation machinery of animal cells.

According to the authors, it is not common to find a macro domain linked to a histone protein, mostly in charge of chromatin regulation than metabolic balancing. Their hypothesis is this just happened by chance, as usual in evolution, and happened to be just fine, since the extended half-life of histones into the nucleus contributed to keep energy consumption of the nucleus down for long periods, in an easy and unexpensive way.

All in all, perhaps the survival of the fittest might be the simplest explanation for a humble histone variant playing an important role in the energy balance between the nucleus and the mitochondria, allowing the animal lineage to survive up until today. Not a lesser feat.

Reference paper:

Guberovic, I., Hurtado-Bagès, S., Rivera-Casas, C. et al. “Evolution of a histone variant involved in compartmental regulation of NAD metabolism”. Nat Struct Mol Biol 28, 1009–1019 (2021). https://doi.org/10.1038/s41594-021-00692-5