CLUH granules coordinate translation of mitochondrial proteins with mTORC1 signaling and mitophagy

The EMBO Journal
David Pla-MartinElena I Rugarli

Abstract

Mitochondria house anabolic and catabolic processes that must be balanced and adjusted to meet cellular demands. The RNA-binding protein CLUH (clustered mitochondria homolog) binds mRNAs of nuclear-encoded mitochondrial proteins and is highly expressed in the liver, where it regulates metabolic plasticity. Here, we show that in primary hepatocytes, CLUH coalesces in specific ribonucleoprotein particles that define the translational fate of target mRNAs, such as Pcx, Hadha, and Hmgcs2, to match nutrient availability. Moreover, CLUH granules play signaling roles, by recruiting mTOR kinase and the RNA-binding proteins G3BP1 and G3BP2. Upon starvation, CLUH regulates translation of Hmgcs2, involved in ketogenesis, inhibits mTORC1 activation and mitochondrial anabolic pathways, and promotes mitochondrial turnover, thus allowing efficient reprograming of metabolic function. In the absence of CLUH, a mitophagy block causes mitochondrial clustering that is rescued by rapamycin treatment or depletion of G3BP1 and G3BP2. Our data demonstrate that metabolic adaptation of liver mitochondria to nutrient availability depends on a compartmentalized CLUH-dependent post-transcriptional mechanism that controls both mTORC1 and G3BP signaling and ...Continue Reading

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Citations

Aug 13, 2020·International Journal of Molecular Sciences·Jianli HeTianshi Wang
Mar 13, 2021·Current Biology : CB·Juncai MaByung-Ho Kang
Jul 7, 2021·Cellular and Molecular Life Sciences : CMLS·Eva-Maria EcklLucas T Jae
Aug 18, 2021·EMBO Reports·Kira MüntjesMichael Feldbrügge

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Methods Mentioned

BETA
Fluorescence
immunoprecipitations
RIP
immunoprecipitation
deubiquitination
transfection
PCR

Software Mentioned

Cufflinks
GraphPad Prism
MaxQuant
DEseq2
Andromeda
Instant Clue
Bioconductor
Ensembl
ImageJ
TopHat2

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