Dietary Inorganic Nitrate Improves Mitochondrial Efficiency in Humans

Abstract

Nitrate, an inorganic anion abundant in vegetables, is converted in vivo to bioactive nitrogen oxides including NO. We recently demonstrated that dietary nitrate reduces oxygen cost during physical exercise, but the mechanism remains unknown. In a double-blind crossover trial we studied the effects of a dietary intervention with inorganic nitrate on basal mitochondrial function and whole-body oxygen consumption in healthy volunteers. Skeletal muscle mitochondria harvested after nitrate supplementation displayed an improvement in oxidative phosphorylation efficiency (P/O ratio) and a decrease in state 4 respiration with and without atractyloside and respiration without adenylates. The improved mitochondrial P/O ratio correlated to the reduction in oxygen cost during exercise. Mechanistically, nitrate reduced the expression of ATP/ADP translocase, a protein involved in proton conductance. We conclude that dietary nitrate has profound effects on basal mitochondrial function. These findings may have implications for exercise physiology- and lifestyle-related disorders that involve dysfunctional mitochondria.

Dietary nitrate supplementation enhances high-intensity running performance in moderate normobaric hypoxia, independent of aerobic fitness

“…These findings are in line with most previous investigations [4,5,22,37], and similar to the results of a recent meta-analysis [6]. The physiological mechanisms underlying the decreased V O2 subsequent to nitrate supplementation have not been fully elucidated, but may be accounted for by: a) an improvement in the efficiency of mitochondrial respiration [35] and/or b) enhanced efficiency of muscle force production [7].…”

“…Tissue oxygenation in the vastus lateralis was also elevated following nitrate supplementation in that study. These findings are supportive of the notion that nitrate supplementation may reduce muscle O2 consumption during exercise in hypoxia, presumably via the aforementioned mitochondrial [35] and/or muscle [7] alterations that also manifest as a reduced V O2. Interestingly, Arnold et al [38] found that runners identified as 'responders' to nitrate supplementation during a 10,000 m TT in moderate hypoxia (FIO2 15.4 %) typically experienced a lower SaO2 during the placebo TT than 'non-responders' (82 vs 84 %).…”

“…Larsen and co-workers [35] reported an improvement in the phosphate/O2 (P/O) ratio (i.e. the amount of ATP produced per mole O2 consumed) in mitochondria harvested from the vastus lateralis of healthy men following three days supplementation with sodium nitrate (0.1 mmol·kg -1 ·d -1 ).…”

“…This suggests that nitrate supplementation may be more likely to enhance NO generation and therefore improve performance in hypoxia relative to normoxia. Moreover, an improvement in mitochondrial [35] and/ or muscle contractile efficiency [7] subsequent to nitrate supplementation which reduces V O2 is likely to be especially advantageous when O2 availability is low. This is supported by the findings of a recent study, in which nitrate supplementation improved tolerance to severe intensity cycling in hypoxia (FIO2 13.1 %) but not normoxia [36].…”

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

“…The Karolinska group showed in a double‐blind crossover trial in healthy volunteers that oral inorganic nitrate supplementation improves oxidative phosphorylation efficiency in skeletal muscle mitochondria. An analysis of mitochondrial function revealed decreased expression of ANT and decreased mitochondrial membrane uncoupling (Larsen et al ., 2011). It has also been proposed that under hypoxic conditions, nitrite may act as the terminal electron acceptor in place of oxygen (Basu et al ., 2008).…”