Presentation description

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disorder characterized by persistent fatigue, immune activation, and metabolic dysfunction. The "itaconate shunt hypothesis" states that chronic immune signaling upregulates ACOD1 (aconitate decarboxylase 1), which converts the TCA cycle metabolite cis-aconitate to itaconate and depletes the former from energy production. To test this mechanism in vivo, we generated zebrafish with heat-shock-inducible overexpression of human ACOD1. ACOD1 larvae were evaluated for locomotor activity and oxygen consumption using the ZebraBox behavioral analysis platform and Oxytherm+R respirometer, respectively. ACOD1 overexpression was linked to both reduced locomotion and decreased oxygen consumption rate. Treatment with bisphosphonate ACOD1 inhibitors (citraconate, etidronate, medronate, propylene diphosphonate) rescued locomotor function. Ongoing studies include LC-MS-based metabolomics of wildtype, ACOD1-expressing, and compound-treated larvae to identify metabolic drivers of fatigue and rescue. To expand the throughput of zebrafish disease modeling and metabolic phenotyping in the lab, we are also building the MIC-Drop-metabolomics platform, which couples high-throughput in vivo CRISPR screening of hundreds of genes with single-larva metabolomics readout. Insights from these works may inform therapeutic development and biomarker discovery in ME/CFS and a wide range of metabolic disorders.