Potential of Mitochondria-Targeted Antioxidants to Prevent Oxidative Stress in Pancreatic β-cells

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.

<p>Reactive Oxygen Species: Drivers of Physiological and Pathological Processes</p>

“… 178 To circumvent this limitation, antioxidants are being conjugated with lipophilic cations so that they can accumulate in mitochondria. 179 Alternatively, human clinical trials regarding dietary supplementation have reported to reduce ROS injury related to aging. 180 Thus, vitamin D supplementation can reduce the risk of hip and other fractures in housebound elderly.…”

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

“…Typical examples of these small molecules are S1QELs and S3QELs [ 145 , 149 ], which do not interfere with the process of oxidative phosphorylation or ATP production [ 144 ]. S1QELs acts at the site I Q of complex I [ 145 , 147 ] while S3QELs acts at the Q site of complex III [ 150 , 151 ]. The usefulness of these suppressors in combating oxidative stress has been tested in certain experimental systems [ 151 , 152 , 153 , 154 ].…”

Targeting mitochondria: a great boon to fight type 2 diabetes

“…However, there is not a decrease in pro-inflammatory cytokines (Demyanenko et al, 2017, p. 1). The antioxidant effect was further confirmed by reductions in mtROS and prevention of mitochondrial fragmentation in INS-1E cells, and in isolated mouse pancreatic islets under high glucose (Plecitá-Hlavatá et al, 2019). Mitochondria-targeted antioxidant peptides such as SS-31 also have beneficial effects in diverse T2D-related alterations.…”