CLUH regulates mitochondrial metabolism by controlling translation and decay of target mRNAs

Abstract

CLUH binds mRNAs implicated in intermediate metabolism and oxidative phosphorylation, but the physiological and molecular significance of these interactions is unclear. Schatton et al. use new constitutive and liver-specific Cluh knockouts to define the function of CLUH in catabolic and energy-converting pathways as a regulator of the translation and stability of target mRNAs.

CLUH couples mitochondrial distribution to the energetic and metabolic status

“…The increase in carnosine (β-alanyl-L-histidine), which has an antioxidant effect (Kohen et al, 1988), might protect cells from the increased ROS production induced by the defective mitochondria in KO cells. We also found an increase of many amino acids, including alanine, glycine, serine, arginine, proline, glutamine, glutamate and aspartate, as also reported by Schatton et al in the liver of E18.5 Cluh-KO embryo and in the serum of Cluh-KO mice that had been starved for 8 weeks (Schatton et al, 2017). This can be related to the dysfunction of the Krebs cycle, as we observed decreased respiration rates when supplying different substrates of the Krebs cycle.…”

“…Frequently, a decrease in the abundance of the respiratory subunits and complex assembly is associated with mtDNA depletion, which was found in the liver and heart of Cluh-KO mice, but not in their kidney and brain tissues (Schatton et al, 2017). In our cellular model, the mtDNA abundance remained unaffected, but the mitochondrial protein synthesis was significantly reduced in the absence of CLUH, suggesting a major alteration of the mitochondrial translation process.…”

“…Indeed, although the fetal development was normal in Cluh-KO mouse, pups died at 0-1 days after birth, and liver analysis at embryonic day (E)18.5, or at 8 weeks for a liver-specific Cluh KO mouse, revealed severe metabolic alterations under starvation conditions (Schatton et al, 2017). Thus, both HeLa cells and mice deleted for Cluh revealed clustered mitochondria and hypersensitivity to glucose starvation.…”

“…Beside the importance of CLUH on mRNA translation of nuclear-encoded mitochondrial proteins (Gao et al, 2014;Sen and Cox, 2016), the evidence that PINK1 and Parkin also control the mRNA translation of the respiratory chain subunits at the outer mitochondrial membrane (Gehrke et al, 2015) suggests that a concerted regulation of all the respiratory components encoded by the nuclear and mitochondrial genomes can be achieved by a crosstalk between CLUH and the PINK-Parkin pathway. Thus, the decrease in the mitochondrial translation machinery in CLUH-KO cells without mtDNA defects raises questions about both the stability of mitochondrial mRNA and the regulation of specific downstream effects on the mRNAs that are targeted by CLUH (Schatton et al, 2017).…”

T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression

“…Mitochondrial biogenesis is controlled by specific transcription factors, such as peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣) (9), which activates mitochondrial DNA (mtDNA) replication, and by RNA binding proteins (RBPs), such as, for example, Y-box-binding protein 1 (YB-1) and clustered mitochondria (cluA/CLU1) homolog (CLUH), which exert posttranscriptional control (10,11). Conversely, mitochondrial dynamics is controlled by mitochondrion-shaping proteins that regulate fusion and fission events.…”