P-379 - Sirtuin- cAMP crosstalk in metabolic diseases: nucleus versus mitochondria

Abstract

Mitochondrial dysfunction in human pathologies make mitochondrial signaling systems attractive therapeutic targets. Sirtuins are deacylases that play a central role in mitochondrial function, metabolic regulation and aging. Indeed, efficient mitochondria and adaptive changes in oxidative metabolism were shown to be coordinated by signaling pathways, activated by physiological stimuli, controlling an intense crosstalk between nucleus and mitochondrial genomes. In this study, SIRT3 or SIRT1 KO as well as wild-type MEFs were incubated with specific activators and inhibitors controlling these signaling pathways. We observed an improvement of mitochondrial function in SIRT3-/- MEFs and SIRT1-/- MEFs by observing a dose- and time-dependent increase in mitochondrial membrane potential. Moreover, no changes were observed for reactive oxidative species formation and an increase in nuclear-encoded mitochondrial genes were observed. Here, we are starting to understand the crosstalk between two major signaling systems in two cell compartments. Pharmacological or alternative therapies offer promising approaches to target and manipulate these systems leading to the maintenance of mitochondrial content and function, and ultimately prevention of cellular dysfunction.