CLUH-dependent RNA granules coordinate mitochondrial catabolic pathways with mTORC1 signaling and mitophagy

ABSTRACT: Mitochondria house anabolic and catabolic processes that must be balanced and rapidly adjusted to meet the cellular demands. CLUH binds mRNAs of nuclear encoded mitochondrial proteins and is highly expressed in the liver, where it regulates metabolic plasticity by an ill-defined mechanism. Here, we show that CLUH-dependent regulation of mitochondrial function is spatially organized through the coalescence of CLUH and its target mRNAs in specific G3BP1-positive granules. These CLUH-dependent granules protect mRNAs involved in mitochondrial energy-converting pathways from decay and define their translational fate to match nutrient availability. CLUH granules suppress premature mTORC1 activation during nutrient deprivation, inhibiting mitochondrial anabolic pathways. Lack of spatial CLUH regulation causes mTORC1 hyperactivation, which impairs mitophagy and triggers cell death. Our data demonstrate that the temporal catabolic adaptation of mitochondria depends on a compartmentalized CLUH-dependent post-transcriptional mechanism that controls mTORC1 signaling and mitochondrial turnover, thus ensuring survival.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

SUBMITTER: Janica Wiederstein  

LAB HEAD: Elena Irene Rugarli

PROVIDER: PXD014098 | Pride | 2020-03-19

REPOSITORIES: Pride