Organ-specific mitochondrial heterogeneity: An under-recognized variable in preclinical drug toxicity screening.

Mitochondria exhibit substantial organ-specific heterogeneity arising from the distinct physiological, metabolic, and functional demands of individual organs. Differences in bioenergetics, oxidative stress handling, calcium homeostasis, and metabolic adaptability may influence mitochondrial responses to pharmacological agents and contribute to organ-selective drug toxicity. However, contemporary preclinical drug toxicity screening continues to rely predominantly on generalized experimental systems that may incompletely capture these organ-specific mitochondrial vulnerabilities. This Perspective proposes integrating organ-adapted mitochondrial physiology into preclinical drug safety evaluation through tissue-relevant cellular models, functional mitochondrial assays, and emerging microphysiological platforms to improve predictive toxicology and strengthen translational relevance.