Mitochondrial Complex I hyperactivation drives PET microplastic-induced intestinal bioenergetic collapse.

Polyethylene terephthalate (PET) microplastics (MPs) are pervasive environmental contaminants with documented human exposure, transporting across intestinal epithelium into the circulatory system and accumulating in multiple organs. This study demonstrates that digestive transformation confers a surface modification on PET MPs, altering their bio-identity and initiating a multilevel pathogenic cascade leading to intestinal dysfunction. Using physiologically relevant particles derived from commercial bottles and a simulated gastrointestinal tract, digested PET MPs inhibit the GLUT2 causing intracellular glucose accumulation and glycolytic disruption, leading to a functional glycolytic blockade, where paradoxical enzyme upregulation results in severely inhibited flux and loss of glucose homeostasis. High-resolution respirometry reveals dysfunctional hyperactivation of mitochondrial Complex I (13.46 ± 7.65 fold, p < 0.0001) as a novel toxic mechanism, driving paradoxical electron transport chain overactivity that culminates in rampant ROS generation (1.89 ± 0.14 fold, p < 0.0001), ATP synthesis shutdown (1.90 ± 0.29 fold, p < 0.01), and decompensated oxidative stress, as evidenced by a significant rise in lipid peroxidation (1.23 ± 0.12 fold, p < 0.01). These disruptions critically impair mitochondrial bioenergetics, initiating a maladaptive metabolic reprogramming that culminates in systemic collapse of mitochondrial metabolism. Integrated multi-omics profiling delineates a self-amplifying mitochondrial metabolic trap, linking proteomic stress to irreversible energetic deficit. These findings establish digestively transformed PET MPs as drivers of metabolic toxicity and provide a mechanistic framework for assessing the health risks of dietary microplastic exposure.