The amazing world of RNA binding proteins regulating the mitochondrial function

FERNÁNDEZ ALVAREZ, ANA JULIA

Congreso; Reunion Anual de Sociedades de Biociencias SAIC SAI SAFIS; 2020

Translational control is essential for proper eukaryotic protein expression and so mRNA metabolism and function must be finely regulated at different levels. The modulation of mRNA nuclear export, stability, rate of translation, and localization is regulated by RNA binding proteins (RBPs) that therefore determine the final amount of synthesized proteins. Some RBPs are essential for the function of all cellular mRNAs, while others control a subset of transcripts coding for proteins implicated in distinctive processes. RBPs make up assemblies denominated membrane-less organelles (MLOs) which concentrate space and temporarily the mRNA molecules necessary to perform a specific function.Mitochondria are dynamic and plastic organelles, which flexibly adapt morphology, ATP production, and metabolic function to meet extrinsic challenges and demands. In the last decade, the posttranscriptional regulation of the expression of nuclear-encoded mitochondrial proteins has emerged as a fast, flexible, and powerful mechanism to shape mitochondrial function and coordinate it with other cellular processes. In fact, several recent studies have highlighted that the fate of mRNAs encoding mitochondrial proteins is dictated by RBPs that orchestrates mitochondrial function during physiological and pathological conditions.In our laboratory we have implicated human RBP Smaug in the regulation of mitochondrial function. Smaug is a conserved translational repressor that recognizes specific RNA motifs present in a large number of mRNAs, including nuclear transcripts that encode mitochondrial enzymes and forms cytosolic MLOs in several organisms and cell types. We demonstrated that the loss of Smaug function affects mitochondrial activity and mitochondrial network morphology. Single molecule FISH reveal that transcripts that encode SDHB and Uqcrc1 associate with Smaug MLOs. In addition, defective Smaug MLO formation affects mitochondrial activity. Finally, rotenone and metformin but not the uncoupler CCCP rapidly induce Smaug MLO dissolution and the release of bounded mRNAs. We propose that Smaug MLOs respond to changes in the energetic metabolism to coordinate the expression of mRNAs that encode key mitochondrial proteins.