Emerging evidence shows that mitochondria fusion/fission imbalance is related to the occurrence of hyperglycemia-induced vascular injury. To study the temporal dynamics of mitochondrial fusion and fission, we observed the alteration of mitochondrial fusion/fission proteins in a set of different high-glucose exposure durations, especially in the early stage of hyperglycemia. The in vitro results show that persistent cellular apoptosis and endothelial dysfunction can be induced rapidly within 12 hours’ high-glucose pre-incubation. Our results show that mitochondria maintain normal morphology and function within 4 hours’ high-glucose pre-incubation; with the extended high-glucose exposure, there is a transition to progressive fragmentation; once severe mitochondria fusion/fission imbalance occurs, persistent cellular apoptosis will develop. In vitro and in vivo results consistently suggest that mitochondrial fusion/fission homeostasis alterations trigger high-glucose-induced vascular injury. As the guardian of mitochondria, AMPK is suppressed in response to hyperglycemia, resulting in imbalanced mitochondrial fusion/fission, which can be reversed by AMPK stimulation. Our results suggest that mitochondrial fusion/fission’s staged homeostasis may be a predictive factor of diabetic cardiovascular complications.

We previously demonstrated that fatty acid-binding protein 3 (FABP3) is significantly upregulated in ischemic neurons, and its inhibition mitigates ischemic brain injury in mice and attenuates mitochondrial damage under rotenone-induced oxidative stress. These findings suggest a potential role for FABP3 in mitochondrial dysfunction in ischemic neurons, although the underlying mechanism remains unclear. In this study, we further investigated the role of FABP3 in mitochondrial injury and apoptosis in ischemic neurons. Our findings indicated that FABP3 deficiency significantly decreased infarct volume following middle cerebral artery occlusion/reperfusion (MCAO/R) in mice, improved cognitive and spontaneous activity deficits, and suppressed BAX activation and mitochondrial translocation, caspase-3 activation, and cytochrome c release. In HT22 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), FABP3 deficiency increased cell viability, reduced apoptosis, and alleviated the loss of mitochondrial membrane potential. Conversely, FABP3 overexpression further exacerbated mitochondrial dysfunction and apoptosis, effects that were partially reversed by the BAX inhibitor BAI1. Furthermore, FABP3 overexpression promoted abnormal mitochondrial lipid accumulation and increased lipid peroxidation. Both the mitochondria-targeted antioxidant MitoQ and the ferroptosis inhibitor Ferrostatin-1 alleviated FABP3 overexpression-induced mitochondrial damage and apoptotic signaling. Collectively, our findings suggest that FABP3 is an important promoter of cerebral ischemia–reperfusion injury. FABP3 may aggravate ischemic neuronal injury by promoting abnormal mitochondrial lipid accumulation and lipid peroxidation, thereby enhancing BAX-dependent mitochondrial apoptotic signaling. Targeting FABP3 may provide a potential therapeutic strategy for neuroprotection in ischemic stroke.