Mcrip2 Regulates the Expression of Mitochondrial Pathways at the Post-transcriptional Level and is Required for Brown Adipose Tissue Function

In response to changing energy demands, mitochondrial networks undergo dynamic remodeling (e.g., biogenesis, mitophagy, fusion or fission, and regulated expression of proteins), to help cells and tissues adapt. Many of these adaptive processes are regulated by the Peroxisome proliferator-activated receptor Gamma Coactivator-1 co-regulators (PGC-1α/β), which work with Estrogen Related Receptors (ERRα/β/γ) to activate the transcription of genes important for mitochondrial biogenesis, oxidative metabolism, and other pathways. In BAT, high levels of PGC-1α and ERRs developmentally endow the tissue with high mitochondrial density and oxidative capacity; moreover, in response to cold, β-adrenergically-activated PGC-1α and ERRs transiently induce the expression of genes within these same pathways. How such transcriptional increases are consolidated into long-term adaptive elevations in genes encoding mitochondrial proteins, and specifically in proteins required for thermogenesis in BAT, is unclear. We hypothesize that post-transcriptional mRNA regulatory mechanisms are co-induced by cold and are necessary for BAT remodeling. We show here that MAPK Regulated Corepressor Interacting Protein 2 ( Mcrip2 ) is a PGC-1/ERR-regulated, cold-inducible gene that enhances BAT oxidative metabolism gene expression at the post-transcriptional level. Transcriptomic and proteomic characterization of BAT collected from WT and Mcrip2 BAT-specific KO mice (Mcrip2 BAT-KO ) indicate that MCRIP2 is required selectively for the expression of genes related to mitochondrial function, particularly genes involved in oxidative metabolism and mitochondrial translation pathways. Accordingly, Mcrip2 BAT-KO mice have lipid-laden BAT, decreased oxidative phosphorylation complex I & II activity, increased sensitivity to cold, and gene-specific defects in cold-induced gene expression compared to WT littermates. Diminished mitochondrial function in mice lacking MCRIP2 in BAT is accompanied by elevated expression of mitochondrial stress response markers. Loss-of-function approaches in brown adipocyte cultures show that MCRIP2 promotes the expression of branched chain amino acid and fatty acid oxidation genes, as well as of uncoupling protein 1 ( Ucp1 ), and that it does so at a post-transcriptional level. Altogether, our findings highlight a critical role for MCRIP2 in building the mitochondrial oxidative capacity necessary for BAT thermogenesis and suggest a pathway by which mitochondrial adaptation to cold exposure, via PGC-1α/β and ERRs, can be regulated at a post-transcriptional level. The work was supported by AHA fellowship 836680 granted to A.W. and NIH grant R01DK128933 funded to N.K. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.