MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

- Research

Graphic design reproduced by permission of Line Hurtado

A new paper published by researchers from the Josep Carreras Leukaemia Research Institute (IJC) and the Programme of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP) reveals a new role for macroH2A1.1. The project was spear-headed by Melanija Posavec Marjanovic and Sarah Hurtado-Bagès, two PhD students enrolled in the Pompeu Fabra UniversityPhD program.

The study provides new information on how differentiating cells adapt to different needs for metabolic activity by modulating their chromatin composition. Specifically, nuclear macroH2A1.1 is shown to be involved in controlling mitochondrial activity in a manner largely independent of gene regulation.

Chromatin is the combination of the DNA, which carries the genetic code and the proteins around which it is tightly wrapped like wool on bobbins. Changes in these proteins can open or close the tight bundles turning gene function off or on.

The Chromatin and Cell Fate Group studies histone variants, which make up some specialized bobbins round which the DNA is wound; the bobbins affect activities in the cell.  In this study on developing muscle cells, they have discovered a previously unknown mechanism by which differentiating cells use a change in chromatin composition to adapt to different needs for metabolic activity as cells go through differentiation.

The histone variant macroH2A1.1 can bind to NAD+ derived metabolites. NAD+ is a fuel for functioning of both the nuclei, where DNA replication and activation of genes occurs, and the mitochondria, the powerhouses of the cell that provide energy for the processes of life (metabolism). 

The nuclei and the mitochondria are different parts of the cell machinery (organelles) that are in separate and compartments.  The nucleus controls genome usage (which genes are switched on) and the mitochondria controls energy metabolism.  It seems likely that cells have evolved ways of coordinating these activities but how they did this was not known given the separation of the two types of organelles.  This work shows that the large structure on macroH2A1.1, the macrodomain, which forms a pocket that binds to other substances is, in this case, binding to a metabolite on the surface of the enzyme PARP and inhibiting its activity. High levels of PARP activity leads to high NAD+ consumption and to low levels of its precursor and visa versa, this has an effect on the pools of NAD+ precursors available both in the nucleus and in the mitochondria.

This work points to macroH2A1.1 being involved in controlling mitochondrial activity, instead of the usual role for histone variants, which to is organize DNA and ultimately affect gene activity.  This role seems to be unique to this histone variant and does not occur other variants in the family that we know so far.

The PARP pathway has been well studied and PARP inhibitors are used to treat various diseases, including but not limited to breast cancer.   This very interesting new role for MacroH2A1.1 could in the future provide another target for more precise drug treatments. 

The Chromatin and Cell Fate Group is located at the Josep Carreras Leukaemia Research Institute (IJC), and also affiliated to the Programme of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain. The group leader is Marcus Buschbeck.