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

Abstract

Mitochondria house anabolic and catabolic processes that must be balanced and adjusted to meet cellular demands. The RNAbinding 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.

SUMOylation-Mediated Response to Mitochondrial Stress

“…During this process, intermediates produced from the mitochondrial metabolism can be used as raw materials for anabolism and signal molecules that regulate cell activity [4]. Increasing numbers of studies are providing evidence to validate the claim that the metabolic activities and functions of mitochondria are triggered by extracellular environmental alterations [5][6][7][8]. The environmental alterations include oxygen, temperature, nutrients, endocrine, toxicity and other cellular stress-induced factors [5][6][7][8].…”

DHX30 coordinates cytoplasmic translation and mitochondrial function contributing to cancer cell survival

“…Hence, a coordination between translational control and metabolic output ultimately involving mitochondrial respiratory functions is expected to contribute to cell homeostasis and fitness 19,20 . However, relatively few proteins and pathways have been established to exert a direct role in balancing cytoplasmic translation initiation with mitochondrial metabolism 21,22 . eIF6 represents a significant example, as it has been clearly shown that it negatively controls 80S monosome assembly, a necessary step for translation initiation, while at the same time playing a critical positive role in mitochondrial functions, as revealed by broad changes in the mitochondrial proteome in eIF6 hemizygous mice [23][24][25] .…”

Smaug membraneless organelles regulate mitochondrial function

“…The role of Smaug orthologues as post-transcriptional regulators of energetic metabolism appears evolutionary conserved as yeast Vts1p –which forms MLOs and prion-like condensates– controls mRNAs linked to nutrient sensing (Chakravarty et al, 2020; She et al, 2017). Translation of nuclear-encoded transcripts at the mitochondrial periphery is known to be regulated by a reduced number of RNA-binding proteins, including the highly conserved factors clustered mitochondria homolog (CLUH) and Pumilio orthologs (reviewed in(D’Amico et al, 2019; Gao et al, 2014; Gehrke et al, 2015; Kopp et al, 2019; Lee & Tu, 2015; Olivas & Parker, 2000; Pla-Martin et al, 2020; Schatton et al, 2017; Schatton & Rugarli, 2018; Vardi-Oknin & Arava, 2019; Wakim et al, 2017) The putative interplay between these pathways and Smaug remains to be investigated.…”