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

David Pla-Martín,Marcus Krüger,Marie-Charlotte Marx,Désirée Schatton,Salim Khiati,Elena I Rugarli,Janica L Wiederstein

doi:10.15252/embj.2019102731

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 ensures survival.

Highlights

Considered as the powerhouse of the cell, mitochondria contribute in several ways to cell and tissue metabolism, by producing biosynthetic intermediates, hosting catabolic reactions, and participating in signaling pathways (Chandel, 2014; Spinelli & Haigis, 2018)
The expression of a subset of mitochondrial proteins involved in oxidative phosphorylation (OXPHOS) and mitochondrial translation is promoted in a mTORC1-dependent manner to enable the production of ATP necessary for protein synthesis, which is an energetically costly process (Morita et al, 2013; Saxton & Sabatini, 2017)
We show that in primary hepatocytes, CLUH assembles with its bound mRNAs in specific RNP particles that function as compartments that coordinate the translation of target mRNAs, and as signaling hubs that control the dynamics of mTORC1 activation and modulate the function of other RNA-binding proteins (RBPs), such as Ras-GTPaseactivating protein SH3 domain-binding proteins 1 and 2 (G3BPs)

Summary

Introduction

Considered as the powerhouse of the cell, mitochondria contribute in several ways to cell and tissue metabolism, by producing biosynthetic intermediates, hosting catabolic reactions, and participating in signaling pathways (Chandel, 2014; Spinelli & Haigis, 2018). To adapt their metabolic function to cellular needs, mitochondria change shape, fuse or divide, interact with other organelles, and are replaced by balanced biogenesis and turnover (Eisner et al, 2018). Elucidating mechanisms that control the dynamic changes of mitochondrial metabolism and turnover to adapt them to energy needs is paramount to understand how organisms survive upon stress and starvation

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