Mitochondrial bioenergetics of metabolic inflammation: Derepressing mitochondrial respiration as a novel therapeutic approach in type-2 diabetes – MitoFLAME

Inflammation is established as a causal factor in developing type-2 diabetes (T2D). We reported that inflammation in T2D arises through the transcription factor Interferon regulatory factor (Irf)-5 in adipose tissue and liver macrophages (Dalmas et al 2015; Alzaid et al 2016). Here, I present preliminary data placing Irf5 as a central mediator of bioenergetic adaptation, repressing mitochondrial respiration to optimise inflammatory polarisation. Accordingly, I aim to interrogate Irf5-dependent mediators of cellular metabolism as sensors of inflammation and novel therapeutic targets. Over three work packages, I first characterise immunogenicity of metabolic signals. Next, in vitro and in vivo screening decipher Irf5-dependent bioenergetic pathways for preclinical evaluation. Lastly, a fully translational work package is dedicated to in vivo therapeutic proof-of-principle studies and evaluating Irf5-mediated inflammation as a predictive biomarker of diabetogenesis.