Abstract
Pancreatic β-cells are vulnerable to oxidative stress due to their low content of redox buffers, such as glutathione, but possess a rich content of thioredoxin, peroxiredoxin, and other proteins capable of redox relay, transferring redox signaling. Consequently, it may be predicted that cytosolic antioxidants could interfere with the cytosolic redox signaling and should not be recommended for any potential therapy. In contrast, mitochondrial matrix-targeted antioxidants could prevent the primary oxidative stress arising from the primary superoxide sources within the mitochondrial matrix, such as at the flavin (IF) and ubiquinone (IQ) sites of superoxide formation within respiratory chain complex I and the outer ubiquinone site (IIIQ) of complex III. Therefore, using time-resolved confocal fluorescence monitoring with MitoSOX Red, we investigated various effects of mitochondria-targeted antioxidants in model pancreatic β-cells (insulinoma INS-1E cells) and pancreatic islets. Both SkQ1 (a mitochondria-targeted plastoquinone) and a suppressor of complex III site Q electron leak (S3QEL) prevented superoxide production released to the mitochondrial matrix in INS-1E cells with stimulatory glucose, where SkQ1 also exhibited an antioxidant role for UCP2-silenced cells. SkQ1 acted similarly at nonstimulatory glucose but not in UCP2-silenced cells. Thus, UCP2 can facilitate the antioxidant mechanism based on SkQ1+ fatty acid anion− pairing. The elevated superoxide formation induced by antimycin A was largely prevented by S3QEL, and that induced by rotenone was decreased by SkQ1 and S3QEL and slightly by S1QEL, acting at complex I site Q. Similar results were obtained with the MitoB probe, for the LC-MS-based assessment of the 4 hr accumulation of reactive oxygen species within the mitochondrial matrix but for isolated pancreatic islets. For 2 hr INS-1E incubations, some samples were influenced by the cell death during the experiment. Due to the frequent dependency of antioxidant effects on metabolic modes, we suggest a potential use of mitochondria-targeted antioxidants for the treatment of prediabetic states after cautious nutrition-controlled tests. Their targeted delivery might eventually attenuate the vicious spiral leading to type 2 diabetes.
Highlights
Type 2 diabetes is characterized by the frequently missing first phase of insulin secretion by pancreatic β-cells, which begins in the prediabetic stage, whereas the second phase of insulin secretion may be prolonged or impaired [1,2,3,4]
Effects of Mitochondria-Targeted Plastoquinone SkQ1 on Superoxide Release to the Mitochondrial Matrix in INS-1E Cells. 1 nmol·l-1 mitochondria-targeted plastoquinone SkQ1 nearly completely suppressed the superoxide release rates Jm to the mitochondrial matrix in intact INS-1E cells (Figures 2(a) and 2(b))
In order to demonstrate whether part of the SkQ1 antioxidant mechanism can originate from the SkQ1 cycling with ion-paired fatty acids, as suggested by Skulachev et al [30, 32] (Figure 1(c)), we silenced the mitochondrial uncoupling protein UCP2 in INS-1E cells (Figures 3(a) and 3(b))
Summary
Type 2 diabetes is characterized by the frequently missing first phase of insulin secretion by pancreatic β-cells, which begins in the prediabetic stage, whereas the second phase of insulin secretion may be prolonged or impaired [1,2,3,4]. The deterioration of β-cells and changes in pancreatic islets, stemming from the pathology-induced dedifferentiation and transdifferentiation of β-cells, have been recently recognized as major contributors to type 2 diabetes etiology. These effectors act in parallel with the typical development of insulin resistance in peripheral tissues, originating from a metabolic, i.e., overnutritioninduced, inflammatory component [4,5,6]. Oxidative stress is usually irreversible, when biological constituents are heavily affected and impaired This may lead to the induction of programmed cell death such as apoptosis [4,5,6,7,8]. This burst represents a redox signal [4]
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