Sonodynamic therapy inhibits palmitate-induced beta cell dysfunction via PINK1/Parkin-dependent mitophagy

Abstract

In type 2 diabetes mellitus (T2DM), the overload of glucose and lipids can promote oxidative stress and inflammatory responses and contribute to the failure of beta cells. However, therapies that can modulate the function of beta cells and thus prevent their failure have not been well explored. In this study, beta cell injury model was established with palmitic acid (PA) to simulate the lipotoxicity (high-fat diet) found in T2DM. Sonodynamic therapy (SDT), a novel physicochemical treatment, was applied to treat injured beta cells. We found that SDT had specific effects on mitochondria and induced transient large amount of mitochondrial reactive oxygen species (ROS) production in beta cells. SDT also improved the morphology and function of abnormal mitochondria, inhibited inflammatory response and reduced beta cell dysfunction. The improvement of mitochondria was mediated by PINK1/Parkin-dependent mitophagy. Additionally, SDT rescued the transcription of PINK1 mRNA which was blocked by PA treatment, thus providing abundant PINK1 for mitophagy. Moreover, SDT also increased insulin secretion from beta cells. The protective effects of SDT were abrogated when mitophagy was inhibited by cyclosporin A (CsA). In summary, SDT potently inhibits lipotoxicity-induced beta cell failure via PINK1/Parkin-dependent mitophagy, providing theoretical guidance for T2DM treatment in aspects of islet protection.

The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

“…Supporting these observations, transcriptomic and proteomic studies on mice and healthy and diabetic human β cells treated in hyperglycemic and hyperlipidemic conditions demonstrated decreased expression of glycolytic, oxidative phosphorylation, and tricarboxylic acid cycle related genes [9,20,26,[29][30][31]. Additionally, both hyperglycemia and hyperlipidemia treatment significantly increased respiration, decreased ATP content, lowered mitochondrial membrane potential, and increased mitochondrial volume, signs that indicate mitochondrial uncoupling and dysfunction [30,[32][33][34]. Another study showed both hyperlipidemia and inflammatory cytokine (IL-1β, TNF-α, IFN-γ) treatment altered mitochondria morphology and dynamics through inhibiting mitochondrial fusion, a response to mitochondrial stress important in maintaining health and respiratory efficiency [35,36].…”

Inhibition of the Low Molecular Weight Protein Tyrosine Phosphatase (LMPTP) as a Potential Therapeutic Strategy for Hepatic Progenitor Cells Lipotoxicity—Short Communication

“…Importantly, LMPTP inhibitor promoted expression of PRKN (Figure 3J) , whereas it did not affect the expression of PINK1 (Figure 3I). Both genes positively regulate mitophagy, which is involved in selective removal of damaged mitochondria and thus participates in mitochondria quality control [28]. In contrast, the result showed that LMPTP inhibitor induced a significant decrease of PGC1A transcript levels in comparison to the CTRL and PA groups ( p < 0.01 and p < 0.001, respectively) (Figure 3K).…”

P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head

“…Could enhancing mitophagy to clear these accumulated mitochondria effectively resist BMSCs stress-induced apoptosis and senescence? Mitophagy mediated by the PINK1-Parkin pathway is the most important way to clear damaged mitochondria 37,38 ; mitochondrial translocation of Parkin is very important to mitophagy 39 , and therefore increasing the content of Parkin in cells can be expected to increase mitochondrial translocation of Parkin and thus enhance mitophagy. Therefore, we used lentiviral vector-encoded Parkinenhanced green fluorescent protein (Lv-Parkin-EGFP) to transfect BMSCs.…”