For patients diagnosed with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) or very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), fasting episodes or high-energy demands remain life threatening. Due to the low incidence, clinical trials for novel LCHADD/VLCADD therapies are limited, and current mouse models recapitulate human symptoms only partially. Here, we report the use of mitochondrial morphology and 3D bioprinted, vascularized tissue models to establish a robust testing platform for dietary-based and experimental treatment approaches. Using this platform, we demonstrated that mitochondrial morphology is strictly regulated by NOX2-driven ROS formation. Treatment of LCHADD/VLCADD-derived fibroblasts with the NOX2-inhibitor naloxone led to the reassembly of mitochondrial structures controlled by DNM1L/MFN2. Using RNA transcriptomics, we identified a pro-fibrotic phenotype in LCHADD and VLCADD patient cells, which impaired vessel formation in fully 3D bioprinted human tissue equivalents. Metabolic supplementation with dietary approaches, which are used in standard therapy, partially improved vascularization. Naloxone induced the strongest improvement, restoring vessel length and network complexity to those of healthy controls, suggesting increased oxidative stress as main driver. Interestingly, naloxone had no effect on healthy fibroblasts, underscoring its safety. Taken together, these findings suggest the opioid antagonist naloxone as a potential rescue medication during LCHADD/VLCADD-driven metabolic crises.