Parkin-mediated mitophagy is negatively regulated by FOXO3A, which inhibits Plk3-mediated mitochondrial ROS generation in STZ diabetic stress-treated pancreatic β cells

Abstract

Diabetes mellitus (DM) is one of the most researched metabolic diseases worldwide. It leads to extensive complications such as cardiovascular disease, nephropathy, retinopathy, and peripheral and central nervous system through an inability to produce or respond to insulin. Although oxidative stress-mediated mitophagy has been reported to play an important role in the pathogenesis of DM, specific studies are still lacking as well as remain highly controversial. Here, we found that Parkin-mediated mitophagy in pancreatic β cells under streptozotocin (STZ)-diabetic stress was induced by Polo-like kinase 3 (Plk3) and inhibited by the transcription factor Forkhead Box O3A (FOXO3A). STZ stress induces mitochondrial recruitment of Parkin through Plk3-mediated mitochondrial reactive oxygen species (ROS) generation, which causes pancreatic cell damage. Conversely, FOXO3A acts as negative feedback to prevent diabetic stress by inhibiting Plk3. Meanwhile, antioxidants including N-acetylcysteine (NAC) and natural COA water scientifically block these mitochondrial ROS and mitochondrial recruitment of Parkin by inhibiting Plk3. Through a 3D organoid ex vivo model, we confirmed that not only ROS inhibitors but also mitophagy inhibitory factors such as 3-MA or Parkin deletion can compensate for pancreatic cell growth and insulin secretion under STZ diabetic stress. These findings suggest that the Plk3-mtROS-PINK1-Parkin axis is a novel mitophagy process that inhibits pancreatic β-cell growth and insulin secretion and FOXO3A and antioxidants may provide new alternatives for effective diabetes treatment strategies in the future.

Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signaling pathway

“…Although there are few reports on its involvement in metabolic diseases, it unveils a crucial potential role. During streptozotocin (STZ)-induced diabetes stress in pancreatic β-cells, Foxo3a inhibits Parkinmediated mitochondrial recruitment and mitophagy, thereby impacting the growth of pancreatic β-cells and insulin secretion [44] . In peritoneal macrophages of diabetic mice, Foxo3a, through acetylation, reduces PINK1-dependent mitophagy and in ammasome activation [45] .…”

SIRT3 alleviates painful diabetic neuropathy by mediating the FoxO3a‐PINK1‐Parkin signaling pathway to activate mitophagy

“… 55 However, in a 3D organoid ex vivo model of pancreatic β cells, after diabetic stress, Parkin is recruited to the mitochondria, Parkin‐mediated mitophagy is induced, and FoxO3a causes a negative feedback loop by inhibiting the Plk3‐PINK1‐Parkin axis for mitophagy. 56 The variations in research findings among different studies could be attributed to differences in cell types, in vivo or in vitro experimental models, and the stage of diabetes being studied (early or late). Extensive research is necessary to investigate the mechanisms responsible for the dysregulation of mitophagy in various diabetic complications.…”

“…Acetylation of FoxO3a induced by palmitate results in decreased PINK1-mediated mitophagy and increased activation of the NLRP3 inflammasome 55. However, in a 3D organoid ex vivo model of pancreatic β cells, after diabetic stress, Parkin is recruited to the mitochondria, Parkinmediated mitophagy is induced, and FoxO3a causes a negative feedback loop by inhibiting the Plk3-PINK1-Parkin axis for mitophagy 56. The variations in research findings among different studies could be attributed to differences in cell types, in vivo or in vitro experimental models, and the stage of diabetes being studied (early or late).…”

Mechanism of action of Huangbaichen Sanwei formulation in treating T2DM based on network pharmacology and molecular docking

“…DM is a chronic metabolic disorder characterized by elevated blood glucose levels (hyperglycemia). [11] With the rapid development of science and technology society, the number of T2DM patients induced by living habits has increased significantly. Hyperglycemia and long-term metabolic disorders in T2DM can lead to serious complications, which imparts burdens on families and society.…”