Repeated PM _{2 .5} Inhalation Exposure Drives a Duration‐Dependent Transition From Mitochondr

ABSTRACT

Fine particulate matter (PM _2.5 ) is a recognized cardiovascular toxicant, yet the exposure duration at which mitochondrial stress responses transition from adaptive to persistently injurious remains poorly defined. Here, we identified a duration‐dependent transition in mitochondrial responses under the present exposure conditions. Female Wistar rats were exposed to PM _2.5 (250 μg/m ³ , 3 h/day) for 1, 7, 14, or 21 days, followed by integrated evaluation of cardiac mitochondrial bioenergetics, redox balance, quality control pathways, and ex vivo cardiac function, with washout validation. Short‐term exposure (1–7 days) elicited transient mitochondrial oxidative stress and activation of adaptive quality control responses without impairing respiratory efficiency, electron transport chain activity, ATP production, or cardiac performance; these changes returned to values comparable to controls after a 24‐h pollutant‐free washout under the present experimental conditions. Under the exposure conditions employed, sustained mitochondrial dysfunction first became evident after 14 days of repeated exposure, characterized by coordinated suppression of mitochondrial respiration, ETC complex activities, and ATP synthesis, accompanied by mitochondrial DNA depletion, impaired biogenesis and quality control signaling, sustained oxidative stress, and intramitochondrial metal accumulation. Notably, mitochondrial and cardiac functional deficits induced after ≥ 14 days persisted despite washout, indicating that these deficits were not restored within the 24‐h recovery period examined, rather than reflecting delayed recovery within this window. Collectively, these findings define a duration‐dependent temporal toxicity progression at which repeated PM _2.5 exposure shifts cardiac mitochondria from transient, recoverable stress responses to persistent bioenergetic impairment under the present experimental conditions providing a mechanistic basis for exposure‐duration–informed cardiovascular hazard characterization.