The mitochondria-targeted antioxidant MitoQ, attenuates exercise-induced mitochondrial DNA damage

Abstract

High-intensity exercise damages mitochondrial DNA (mtDNA) in skeletal muscle. Whether MitoQ - a redox active mitochondrial targeted quinone - can reduce exercise-induced mtDNA damage is unknown. In a double-blind, randomized, placebo-controlled design, twenty-four healthy male participants consisting of two groups (placebo; n = 12, MitoQ; n = 12) performed an exercise trial of 4 x 4-min bouts at 90–95% of heart rate max. Participants completed an acute (20 mg MitoQ or placebo 1-h pre-exercise) and chronic (21 days of supplementation) phase. Blood and skeletal muscle were sampled immediately pre- and post-exercise and analysed for nuclear and mtDNA damage, lipid hydroperoxides, lipid soluble antioxidants, and the ascorbyl free radical. Exercise significantly increased nuclear and mtDNA damage across lymphocytes and muscle ( P < 0.05), which was accompanied with changes in lipid hydroperoxides, ascorbyl free radical, and α-tocopherol ( P < 0.05). Acute MitoQ treatment failed to impact any biomarker likely due to insufficient initial bioavailability. However, chronic MitoQ treatment attenuated nuclear ( P < 0.05) and mtDNA damage in lymphocytes and muscle tissue ( P < 0.05). Our work is the first to show a protective effect of chronic MitoQ supplementation on the mitochondrial and nuclear genomes in lymphocytes and human muscle tissue following exercise, which is important for genome stability.

Targeted Antioxidants in Exercise-Induced Mitochondrial Oxidative Stress: Emphasis on DNA Damage

“…Although this was demonstrated in an animal model, it supports the notion that targeted antioxidants may have therapeutic benefits in mitochondrial dysfunction scenarios. Indeed, our recent work [ 119 ] failed to detect any changes in basal mtDNA damage following chronic MitoQ supplementation; however, it did reduce exercise-induced mtDNA damage. We propose that the use of MitoQ may be limited in healthy individuals with low basal oxidative damage [ 11 , 192 ]; however, targeted supplementation may show efficacy in conditions characterised by chronic oxidative stress and/or mitochondrial dysfunction [ 193 , 194 , 195 ].…”

“…Fogarty and colleagues [ 118 ] were the first to demonstrate the impact of exercise on mtDNA by showing that isolated and maximal contractions increased mitochondrial 8-hydroxy-2-deoxyguanosine concentration in vastus lateralis muscle tissue. More recently, we have demonstrated an increase in global mtDNA damage in peripheral blood mononuclear cells and skeletal muscle (as quantified using LA-qPCR) following high-intensity intermittent exercise [ 119 ]. It is highly likely the observed mtDNA damage originated from O 2 − /H 2 O 2 -derived mechanisms, stemming from their ability to react with accessible transition metals to produce damaging hydroxyl free radical species via Fenton chemistry (H 2 O 2 + Fe 2+ → Fe 3+ + − OH + ·OH [ k ~ 76 M −1 s −1 ]; H 2 O 2 + Cu + → Cu 2+ + − OH + ·OH [ k ~ 4.7 × 10 3 M −1 s −1 ]) [ 120 ].…”

“…Furthermore, it appears evident that contraction-induced superoxide production is largely derived from non-mitochondrial sources; specifically NOX2 due to agonist activation (e.g., angiotensin II, cytokines, and mechanical stress) [ 125 , 126 , 127 ]. Notwithstanding the potential for delayed mitochondrial redox dynamics, collectively, the apparent decrease in exercise-mediated mitochondrial O 2 − /H 2 O 2 production as suggested by Goncalves et al [ 69 ], in tandem with the observed increase in mtDNA damage [ 118 , 119 ], presents a major paradoxical juxtaposition of our understanding of mitochondrial redox dynamics in the context of exercise. While much of the topological research of mitochondrial O 2 · − /H 2 O 2 generation has focused on the specific complexes of the respiratory chain [ 69 , 72 ], others have shown correlations between mitochondrial H 2 O 2 generation and P 66Shc -FOXO3a expression in an intensity-dependent manner in the skeletal muscle of mice [ 128 , 129 ].…”

“…To help address this, we recently used long amplicon-qPCR to ascertain the effect of high-intensity intermittent exercise on mitochondrial DNA. Following 4 × 4-minute bouts of exercise, we observed an increase in mtDNA damage (lymphocytes and muscle tissue), and detectable changes in lipid peroxidation and the ascorbyl free radical; some of which was mitigated by chronic MitoQ supplementation (20 mg/day for 3 weeks [ 119 ]). In both instances, the exercise-induced mtDNA damage is likely initiated by: (i) inhibiting repair; (ii) increasing H 2 O 2 production; and/or (iii) increasing the labile redox-active transition metal pool via hydroxyl (and potentially peroxynitrite-derived) radicals [ 120 , 122 ].…”

“…and G.W.D. received MitoQ product from MitoQ ® to conduct one study mentioned within Williamson et al [ 119 ].…”