2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction

This study reports accumulation of larger lipid droplets in an adipocyte specific manner upon loss of CLPP. The mitochondria in KO BAT have mild respiratory chain deficiency but no difference in respiratory output at tissue and cellular level. Omics analysis reveals that loss of CLPP leads to tissue remodeling, and is accompanied by pertinent cytoskeletal changes. The metabolite, 2-hydroxyglutarate accumulates in KO tissue and cells and is possibly produced by the moonlighting function of PHGDH. We further identify 2-HG H3K4me3 methylation changes in epigenome being likely contributing to larger lipid droplets. The study also reports that 2HG mediated whitning is coupled to nuclear softening and changes in nuclear mechanics. Overall design: The experiment involved RNA sequencing for BAT (brown adipose tissue) tissue of different genotypes for mice. In order to assess global changes in BAT of mice upon CLPP loss, we namely, WT , full body KO, adipose specific AKO and brown adipose specific BKO mice. This experiment was aimed at determining the BAT -autonomous and non - atonomous changes upon CLPP loss mediated mitochondrial dysfunction.