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 NOD-like 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.
Highlights
Excessive caloric or fat intake leading to obesity has been associated with beta cell dysfunction, and subsequently insulin resistance and type 2 diabetes (T2D) in human
Previous studies showed that treatment with high glucose and palmitate induced mitochondrial rho GTPase 1 (Miro1) degradation via a Ca2+-dependent pathway (7)
In this study, using islet-specific Miro1-KO (IKO) mice, we identified Miro1 in pancreatic beta cell as a negative regulator of High fat diet (HFD)-induced mitophagy deficiency, inflammatory responses, leading to beta cell secretory dysfunction
Summary
Excessive caloric or fat intake leading to obesity has been associated with beta cell dysfunction, and subsequently insulin resistance and T2D (type 2 diabetes) in human. Together with deficient mitophagy, are both associated with chronic inflammation and insulin resistance [3]. Insulin resistance, inflammation and pancreatic cell dysfunction are common pathological events in obese individuals [4]. In-depth research has been done in this area, the occurrence of complex and associated cell events and related behaviors in vivo connecting mitochondrial function and perturbed insulin secretion in T2D are not well understood. It has been found that before the onset of mitophagy, Cells block mitochondrial motility by causing mitochondrial Rho GTPase (Miro) degradation and ubiquitination of mitochondrial proteins to promote their identification and recruitment to autophagosomes [11,12,13,14]. A deficiency in Miro1-mediated mitophagy triggers triggers mtROS(mitochondrial ROS)induced NLRP3 dependent pro-inflammatory responses and is linked to T2D diseases in vitro [12, 15] [9, 16, 17]
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