Scope Saturated free fatty acids (FFAs) induce hepatocyte lipotoxicity, wherein oxidative stress–associated mitochondrial dysfunction is mechanistically involved. Chlorogenic acid (CGA), a potent antioxidant and anti-inflammatory compound, protects against high-fat-diet-induced oxidative stress and mitochondrial dysfunction in liver. This study investigates whether CGA protects against FFA-induced hepatocyte lipotoxicity via the regulation of mitochondrial fission/fusion and elucidates its underlying mechanisms. Methods and results AML12 cell, a non-transformed hepatocyte cell line, is treated with palmitate. Here, it is shown that CGA prevents palmitate-induced lipotoxicity by activation of SIRT1 regulated mitochondrial morphology. CGA treatment mitigates oxidative stress and mitochondrial dysfunction, as evidenced by a decrease in reactive oxygen species (ROS) production, and an increase in mitochondrial mass and mitochondrial membrane potential. CGA also significantly decreases Bax expression and thereby reduces mitochondria-mediated caspase-dependent apoptosis. Mechanistically, CGA attenuates ROS-induced mitochondrial fragmentation by inhibiting dynamin-related protein 1 (Drp1) and enhancing Mfn2 expression. In contrast, the inhibitory effects of CGA on the generation of mitochondrial ROS and Drp1 are blocked by siRNA knockdown of SIRT1. Conclusion Collectively, these findings show that supplementation with CGA protects hepatocytes from FFA-induced lipotoxicity through activation of SIRT1, which reverses the oxidative stress and dysfunction of mitochondrial biogenesis directly.
Yue He,Man Shu,Zhimin Li,Yun Liu,Ziyang Xu,Kelie Wang,Yu Zhang,Teliang Lu
Diabetes mellitus (DM)-associated hyperglycemia disrupts vascularized bone regeneration through mitochondrial dysfunction in repair-related cells and hindering scaffold-mediated bone defect repair. To overcome this challenge, we developed an innovative 3D-printed β-tricalcium phosphate scaffold co-doped with zinc and silicon ions (Zn/Si-TCP). In vitro evaluations revealed that Zn/Si-TCP significantly enhanced cellular viability of both endothelial cells and osteoblasts under hyperglycemic conditions, achieving this through dual mechanisms: (1) effective reactive oxygen species (ROS) scavenging (35 % reduction), and (2) restoration of mitochondrial homeostasis, as demonstrated by 1.5-fold upregulation of mitochondrial fusion protein Mfn1 and 0.6-fold downregulation of fission protein Drp1. The scaffold notably improved mitochondrial function, enhancing membrane potential by 1.4-fold and boosting ATP generation by 1.2-fold. These synergistic effects translated to superior biological performance, with 1.5-fold enhancement in angiogenic capacity (tube formation assay) and 1.9-fold increase in osteogenic activity (ALP assay). In vivo studies in a diabetic rat calvarial defect model demonstrated the remarkable efficacy of Zn/Si-TCP scaffolds, which achieved a 4.6-fold increase in vascular density and a 2.0-fold improvement in bone volume fraction (BV/TV) compared to undoped TCP controls at 8 weeks post-implantation, indicating successful vascularized bone reconstruction facilitated by Zn/Si-TCP scaffolds. This study establishes a new paradigm in diabetic bone repair by developing a dual-functional scaffold that coordinately promotes angiogenesis and osteogenesis through mitochondrial homeostasis regulation.
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