Is REDD1 a metabolic double agent? Lessons from physiology and pathology.

The Akt/mTOR signaling pathway governs macromolecules synthesis, cell growth and metabolism in response to nutrients and growth factors. REDD1 is a conserved and ubiquitous protein, which is transiently induced in response to multiple stimuli. Acting like an endogenous inhibitor of the Akt/mTOR signaling pathway, REDD1 protein has been shown to regulate cell growth, mitochondrial function, oxidative stress and apoptosis. Recent studies also indicate that timely REDD1 expression limits Akt/mTOR-dependent synthesis processes to spare energy during metabolic stresses, avoiding energy collapse and detrimental consequences. In contrast to this beneficial role for metabolic adaptation, REDD1 chronic expression appears involved in the pathogenesis of several diseases. Indeed, REDD1 expression is found as an early biomarker in many pathologies including inflammatory diseases, cancer, neurodegenerative disorders, depression, diabetes and obesity. Moreover, prolonged REDD1 expression is associated with cell apoptosis, excessive ROS production and inflammation activation leading to tissue damages. In this review, we decipher several mechanisms that make REDD1 a likely metabolic double agent depending on its duration of expression in different physiological and pathological contexts. We also discuss the role played by REDD1 in the crosstalk between the Akt/mTOR signaling pathway and the energetic metabolism.