Primary and secondary mitochondrial disorders are both complex groups of diseases with many aetiologies, and diagnosis is challenging due to clinical and genetic heterogeneity. For many of these disorders, treatment is limited and often purely symptomatic. A significant impediment in determining the efficacy and viability of treatment is the lack of a clinical biomarker that is both diagnostic and can predict disease severity. Recently, the mitokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) have been established as biomarkers of cellular stress and mitochondrial dysfunction in patients with primary mitochondrial disease. Our project aims to investigate the suitability of these mitokines as both diagnostic and monitoring biomarkers for a disorder causing secondary mitochondrial dysfunction, Rett syndrome (RTT). Firstly, we will determine if FGF21 and GDF15 can predict disease course in a Mecp2T158A RTT mouse model. Secondly, we will investigate if these mitokines are differentially expressed in the blood of human females with RTT (relative to a control population) and determine if they are prognostic biomarkers. Finally, we will utilise an integrative, multi-omics approach (proteomics, metabolomics, and transcriptomics) to better understand the pathophysiology of disease and identify novel biomarkers and drug targets. This ultimately will assist in identifying improved therapeutic options for individuals with RTT.