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Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species (ROS) or inadequate antioxidant protection. ROS are produced through several mechanisms in cells including during mitochondrial oxidative phosphorylation. Increased mitochondrial-derived ROS are associated with mitochondrial dysfunction, an early event in age-related diseases such as Alzheimer's diseases (ADs) and in metabolic disorders including diabetes. AD post-mortem investigations of affected brain regions have shown the accumulation of oxidative damage to macromolecules, and oxidative stress has been considered an important contributor to disease pathology. An increase in oxidative stress, which leads to increased levels of superoxide, hydrogen peroxide and other ROS in a potentially vicious cycle is both causative and a consequence of mitochondrial dysfunction. Mitochondrial dysfunction may be ameliorated by molecules with antioxidant capacities that accumulate in mitochondria such as carotenoids. However, the role of carotenoids in mitigating mitochondrial dysfunction is not fully understood. A better understanding of the role of antioxidants in mitochondrial function is a promising lead towards the development of novel and effective treatment strategies for age-related diseases. This review evaluates and summarises some of the latest developments and insights into the effects of carotenoids on mitochondrial dysfunction with a focus on the antioxidant properties of carotenoids. The mitochondria-protective role of carotenoids may be key in therapeutic strategies and targeting the mitochondria ROS is emerging in drug development for age-related diseases.

Mitochondria are important (patho)physiological sources of reactive oxygen species (ROS) that mediate mitochondrial dysfunction and phospholipid oxidation; an increase in mitochondrial content of oxidized phospholipid (OxPL) associates with cell death. Previously we showed that the circulating OxPL 1-palmitoyl-2-(5’-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) increases in patients with Alzheimer’s disease (AD), and associates with lower plasma antioxidant oxocarotenoids, zeaxanthin, and lutein. Since oxocarotenoids are metabolized in mitochondria, we propose that during AD, lower concentrations of mitochondrial zeaxanthin and lutein may result in greater phospholipid oxidation and predispose to neurodegeneration. Here, we have investigated whether non-toxic POVPC concentrations impair mitochondrial metabolism in differentiated (d)SH-SY5Y neuronal cells and whether there is any protective role for oxocarotenoids against mitochondrial dysfunction. After 24 hours, glutathione (GSH) concentration was lower in neuronal cells exposed to POVPC (1–20μM) compared with vehicle control without loss of viability compared to control. However, mitochondrial ROS production (determined by MitoSOX oxidation) was increased by 50% only after 20μM POVPC. Following delivery of lutein (0.1-1μM) and zeaxanthin (0.5-5μM) over 24 hours in vitro, oxocarotenoid recovery from dSH-SY5Y cells was > 50%. Co-incubation with oxocarotenoids prevented loss of GSH after 1μM but not 20μM POVPC, whereas the increase in ROS production induced by 20μM POVPC was prevented by lutein and zeaxanthin. Mitochondrial uncoupling increases and ATP production is inhibited by 20μM but not 1μM POVPC; carotenoids protected against uncoupling although did not restore ATP production. In summary, 20μM POVPC induced loss of GSH and a mitochondrial bioenergetic deficit in neuronal cells that was not mitigated by oxocarotenoids.

Individuals with chronic kidney disease (CKD) and periodontitis as a co-morbidity have a higher mortality rate than individuals with CKD and no periodontitis. The inflammatory burden associated with both diseases contributes to an increased risk of cardiovascular and all-cause mortality. We previously demonstrated that periodontitis is associated with increasing circulating markers of inflammation and oxidative stress. We propose that inflammatory oxidised phosphocholines may contribute to the increased risk of cardiovascular disease in patients with CKD. However, the analysis of oxidised phospholipids has been limited by a lack of authentic standards for absolute quantification. Here, we have developed a comprehensive quantification liquid chromatography-mass spectrometry-based multiple reaction monitoring method for oxidised phospholipids (including some without available authentic species) that enables us to simultaneously measure twelve oxidised phosphatidylcholine species with high levels of sensitivity and specificity. The standard curves for commercial standards 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphatidylcholine (PGPC); 1-palmitoyl-2-(9′-oxo-nonanoyl)-sn-glycero-3-phosphatidylcholine (PONPC), 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphatidylcholine (PAzPC) and 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphatidylcholine (POVPC), were linear with a correlation coefficient greater than 0.99 for all analytes. The method is reproducible, with intra- and inter-day precision <15%, and accuracy within ±5% of nominal values for all analytes. This method has been successfully applied to investigate oxidised phosphatidylcholine in plasma from CKD patients with and without chronic periodontitis and the data that was obtained has been compared to plasma from healthy controls. Comparative analysis demonstrates altered chain fragmented phosphatidylcholine profiles in the plasma samples of patients with CKD and periodontitis as a co-morbidity compared to healthy co