Inhibition of Miro1 disturbs mitophagy and pancreatic β-cell function interfering insulin release via IRS-Akt-Foxo1 in diabetes

Abstract

Mitochondrial function is essential to meet metabolic demand of pancreatic beta cells respond to high nutrient stress. Mitophagy is an essential component to normal pancreatic β-cell function and has been associated with β-cell failure in Type 2 diabetes (T2D). Our previous studies have indicated that mitochondrial Rho (Miro) GTPase-mediated mitochondrial dysfunction under high nutrient stress leads to NODlike receptor 3 (NLRP3)-dependent proinflammatory responses and subsequent insulin resistance. However, the in vivo mechanism by which Miro1 underlies mitophagy has not been identified. Here we show firstly that the expression of Miro is reduced in human T2D and mouse db/db islets and in INS-1 cell line exposed to high glucose and palmitate. β-cell specific ablation of Miro1 (Miro1f/f: Rip-cre mice, or (IKO) under high nutrient stress promotes the development of hyperglycemia. β-cells from IKO mice display an inhibition of mitophagy under oxidative stress and induces mitochondrial dysfunction. Dysfunctional mitophagy in IKO mice is represented by damaged islet beta cell mitochondrial and secretory capacity, unbalanced downstream MKK-JNK signalling without affecting the levels of MEK, ERK or p38 activation and subsequently, impaired insulin secretion signaling via inhibition IRS-AKT-Foxo1 pathway, leading to worsening glucose tolerance in these mice. Thus, these data suggest that Miro1 may be responsible for mitophagy deficiency and β-cell dysfunction in T2D and that strategies target Miro1 in vivo may provide a therapeutic target to enhance β-cell mitochondrial quality and insulin secretion to ameliorate complications associated with T2D.

Miro proteins prime mitochondria for Parkin translocation and mitophagy

“…However, recent data suggest that although Miro deletion affects mitochondrial distribution and motility, the mitochondria retain functionality and membrane potential (Nguyen et al , ; López‐Doménech et al , ) indicating that the loss of Miro per se does not cause mitochondrial depolarisation (Fig E), which is one of the major causes of mitochondrial removal. In line with our results, Chen et al () showed recently that loss of Miro1 selectively in pancreatic beta cells inhibited mitophagy in vivo .…”

β-cell autophagy: Mechanism and role in β-cell dysfunction

“…The role of mitochondria movement in mitophagy of pancreatic β-cells has also been reported. Participation of Miro1, a mitochondrial outer membrane protein mediating the anchoring of kinesin-related protein 5 (KIF5) to mitochondria, in mitophagy of β-cells was reported [62].…”

The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions

“…In obese and T2D patients, the substances secreted by dysfunctional mitochondria into the cytoplasm often serve as DAMPs, which activate the NLRP3 inflammasome. Moreover, a diet rich in fats and glucose induces the production of mitochondrial ROS owing to Miro1-induced effects on mitochondria in pancreatic β cells; these effects consequently cause an NLRP3-induced inflammatory response, thereby impairing insulin production [102,103]. Furthermore, thioredoxin (TRX)-interacting protein (TXNIP) disassociation causes the activation of NLRP3 inflammasomes [104,105].…”