Effect of a mitochondrial‐targeted coenzyme Q analog on pancreatic β‐cell function and energetics in high fat fed obese mice

Abstract

We recently reported that mitoquinone (mitoQ, 500 μmol/L) added to drinking water of C57BL/6J mice attenuated weight gain and reduced oxidative stress when administered to high‐fat (HF) fed mice. Here, we examined the effects of mitoQ administered to HF fed mice on pancreatic islet morphology, dynamics of insulin secretion, and islet mitochondrial metabolism. C57BL/6J mice were fed HF for 130 days while we administered vehicle (cyclodextrin [CD]) or mitoQ added to the drinking water at up to 500 μmol/L. MitoQ‐treated mice vs vehicle gained significantly less weight, expended significantly more energy as determined by indirect calorimetry, and trended to consume less (nonsignificant) food. As we and others reported before, mitoQ‐treated mice drank less water but showed no difference in percent body fluid by nuclear magnetic resonance. Circulating insulin and glucose‐stimulated insulin secretion by isolated islets were decreased in mitoQ‐treated mice while insulin sensitivity (plasma insulin x glucose) was greater. Islet respiration as basal oxygen consumption (OCR), OCR directed at ATP synthesis, and maximal uncoupled OCR were also reduced in mitoQ‐treated mice. Quantitative morphologic studies revealed that islet size was reduced in the mitoQ‐treated mice while visual inspection of histochemically stained sections suggested that mitoQ reduced islet lipid peroxides. MitoQ markedly improved liver function as determined by plasma alanine aminotransferase. In summary, mitoQ treatment reduced the demand for insulin and reduced islet size, likely consequent to the action of mitoQ to mitigate weight gain and improve liver function.

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

“…We can speculate how to translate the obtained data into a use of SkQ1 for the possible prevention of oxidative stress in pancreatic β -cells in vivo [24, 25]. In accordance with currently available data [30–36] and our basic screening, we can speculatively predict that in intact β -cells, SkQ1 might have a beneficial antioxidant role in the postprandial (fed) state, whereas it will not be manifested during fasting.…”

“…Also, an enhanced antioxidant capacity within the matrix may be effectively transferred to the cytosol as well, where this may exert the antioxidant effect in the cytosol, despite the antioxidant agents being located in the mitochondrial matrix [17, 22, 24, 25]. This principle can be applied to the action of antioxidants targeted to the mitochondrial matrix [24–40]: when the cytosolic antioxidant mechanisms and redox buffers do not need to deal with the excessive ROS released from mitochondria to the cytosol, they have a spare capacity, which can produce a stronger antioxidant action in the cell cytosol.…”

“…The mitochondria-targeted antioxidants of type (ii) (blockers of sources) typically interfere with the sites of superoxide formation there but do not extensively influence the primary ROS formation or redox regulations within the cytosol [17, 22, 24, 25, 34].…”

Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

“…Mitochondria are traditionally reported as a profound source of oxidative stress in β-cell pathology (216). This can be deduced also from the effects of mitochondrial matrix-targeted antioxidants (126, 182).…”

The Antioxidant Moiety of MitoQ Imparts Minimal Metabolic Effects in Adipose Tissue of High Fat Fed Mice

“…Indeed, it has now been shown in several studies that dTPP+ elicits its own effects, suggesting that many of the beneficial effects previously attributed to MitoQ, may have been driven by the dTPP+ cation. Examples include studies that observed reductions in body weight and fat mass in mice fed a HFD in comparison to mice administered a control agent such as ethanol or cyclodextrin, rather than dTPP+ or dTPP+ complexed with cyclodextrin (Fink et al, 2014, 2017; Imai et al, 2018).…”