Editors' ChoiceMetabolism

CLUHing in mitochondria to starvation

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Science Signaling  12 May 2020:
Vol. 13, Issue 631, eabc6690
DOI: 10.1126/scisignal.abc6690

The RNA-binding protein CLUH helps reprogram hepatocyte mitochondria in response to starvation.

Whereas nutrients stimulate mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic pathways, starvation inhibits mTORC1 signaling, promotes catabolic pathways, and rewires mitochondrial metabolism. Clustered mitochondria homolog (CLUH) is an RNA-binding protein that promotes the stability and translation of transcripts encoding mitochondrial proteins and plays an important role in the metabolic adaption of the mouse liver to starvation. Pla-Martín et al. found that CLUH, its mRNA substrates, and other RNA binding proteins, formed cytoplasmic granules in hepatocytes. These ribonucleoprotein (RNP) particles were distributed throughout the cytoplasm but coalesced around the nucleus and colocalized with mTOR when mice or primary hepatocytes were starved. Although the RNA-binding proteins G3BP1 and G3BP2 are components of stress granules, CLUH-positive RNPs containing G3BP1 and G3BP2 were distinct from stress granules in HeLa cells, and CLUH-containing RNPs formed even when G3BP1 and G3BP1 were depleted. Experiments in hepatocytes from wild-type and CLUH-knockout mice showed that, under fed conditions, CLUH promoted the stability and translation of transcripts encoding proteins required for mitochondrial translation; however, during starvation, it promoted the stability and translation of transcripts associated with catabolic pathways. In primary hepatocytes and mice, CLUH was required for the suppression of mTORC1 signaling and protection from apoptosis under starvation conditions. Whole livers and hepatocytes from CLUH-knockout mice showed increased autophagy and reduced mitophagy under fed conditions, and the mTORC1 inhibitor rapamycin restored mitophagy in hepatocytes and embryonic fibroblasts from CLUH-knockout mice. Rapamycin or the depletion of G3BP1 or G3BP2 rescued the mitochondrial clustering phenotype in CLUH-knockout mice and CLUH-depleted COS-7 cells. These findings identify CLUH-containing RNPs as being important for coordinating mTORC1 signaling with the mitochondrial adaption to nutrient availability in hepatocytes.

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