Novel Biomarkers of Disorders Causing Secondary Mitochondrial Dysfunction

Abstract

The diagnosis and monitoring of rare diseases relies on the quantification of disease-associated biomarkers. Primary mitochondrial disorders (PMD) have benefited from biomarker research, with studies showing that mitokines (fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15)) are elevated in individuals with PMDs. Given that mitokine elevations may represent a protective response to oxidative stress, increases may also occur in disorders causing secondary mitochondrial dysfunction (SMD), including fatty acid oxidation defects (FAODs), organic acidaemias/acidurias (OAs), and Rett syndrome (RTT). This thesis employed both targeted and untargeted analytical approaches to investigate biomarkers associated with SMD (with a particular focus on RTT). The initial study showed higher mitokine concentrations in individuals with FAODs and OAs compared to controls using enzyme-linked immunosorbent assay. This work was expanded to RTT where mitokine concentrations were measured in both a murine model and in humans. Elevated mitokine levels were observed in affected female mice relative to wild-type (WT) controls. However, the same mitokines were not elevated in affected male mice when compared to WT controls. Mitokine concentrations in female humans with RTT were increased when compared to the unaffected human controls; however, these elevations correlated with sodium valproate therapy. Lastly, untargeted multi-omic analysis (transcriptomic, proteomic, phosphoproteomic, and metabolomic) of blood from individuals with RTT identified enrichment of mitochondrial and ribosomal pathways. Differential correlation network analysis suggested a complex interaction between immune-related and neuronal molecules that may underlie altered glutamatergic signalling. Overall, this body of work highlights the use of both targeted and untargeted methodologies to investigate biomarkers and provides functional insights into the pathophysiology underpinning RTT.