Mitochondrial Gene Networks in Opioid Use Disorder: Multi-omic Evidence for Pathway-Specific Risk and Resilience

Opioid use disorder (OUD) is a heritable, chronic relapsing condition, but the molecular pathways linking genetic risk to disease remain unclear. Using FinnGen GWAS data for opioid-related disorder (F11) as a genetic proxy, we integrated multi-omic quantitative trait loci for 1,136 mitochondrial genes, including methylation, expression, and protein QTLs. Using summary-data-based Mendelian randomization (SMR) with HEIDI filtering followed by Bayesian colocalization, we prioritized a fixed set of 13 mitochondrial genes with evidence of shared genetic regulation with the F11 phenotype. These signals converged on two pathway axes: fatty-acid β-oxidation (e.g., CPT2 and HADHB), for which genetically predicted higher transcript levels were associated with lower risk, and mitochondrial translation (e.g., MRPL21, MRPS17 and MTIF3), for which higher expression was associated with higher risk. The prioritized genes showed prominent expression across mesocorticolimbic and limbic circuits and exhibited coordinated expression with canonical opioid-system genes (including OPRM1 and PENK) in human brain datasets. To provide cross-species support, we evaluated selected candidates in a chronic morphine exposure and naloxone-precipitated withdrawal model in male C57BL/6J mice (n = 6/group), combining behavioural scoring with qPCR in nucleus accumbens (NAc), prefrontal cortex (PFC) and hippocampus (HIP), and Western blotting in NAc. In morphine-withdrawn mice, Cpt2 and Hadhb were downregulated and Mrpl21, Mrps17 and Mtif3 were upregulated across regions; NAc Western blots corroborated reduced CPT2 and increased MRPL21/MRPS17 protein abundance. Together, these results implicate mitochondrial fatty-acid oxidation and translation machinery as genetically supported components of opioid-related disorder liability and motivate mechanistic studies targeting mitochondrial energetics in addiction-relevant circuits.