Metabolomics of mitochondrial disease

The altered human serum metabolome induced by a marathon

“…Furthermore, the elevated concentrations of pyruvic acid observed in the post-marathon samples were anticipated since it is an end-product of the glycolysis pathway which feeds into the TCA cycle for further ATP production (Salway, 2012). This is confirmed by the accumulation of various TCA cycle intermediates such as α-ketoglutaric acid, succinic acid, citric acid, fumaric acid and malic acid (Qiang, 2015), which also indicate the accumulation of circulating NADH/FADH2 molecules (Esterhuizen et al, 2017) as a result of a saturated ETC activity. It is also important to mention that many of the aforementioned carbohydrate metabolites, along with elevated concentrations of mannose (Hu et al, 2016), sorbose (Guzik and Stachowicz, 2016), mannitol (McNutt, 2000), tagatofuranose (Kroger et al, 2006), and threonic acid (an ascorbic acid derivative) (Simpson and Ortwerth, 2000), are…”

“…Nevertheless, irrespective of their origins, these OCFAs are ultimately catabolized to propionyl-CoA (Pfeuffer and Jaudszus, 2016), hence the elevated β-hydroxypropionic acid observed in the post-10 marathon serum. The elevated concentrations of β-hydroxybutyric acid and acetoacetic acid are anticipated, as these are alternative fuel substrates for the brain (Cahill and Vech, 2003) and skeletal muscles (Holloszy and Coyle, 1984) in hypoglycemic states, and could also be an indication of an imbalanced redox state (Esterhuizen et al, 2017;Salway, 2012). Furthermore, the post-marathon elevations of malonic acid typically indicate the accumulation of malonyl-CoA, which is a long-chain fatty acid (LCFA) transport inhibitor (Salway, 2012) and could therefore be an additional reason for the increased cytosolic LCFAs (palmitic acid, palmitoleic acid, 11-eicosenoic acid, 11,14-eicosadienoic acid, myristoleic acid, α-linolenic acid, linoleic acid and oleic acid).…”

“…Previous metabolomics studies have indicated elevated concentrations of various carbohydrate/glycolysis metabolite intermediates, indicative of free glucose utilization as the preferred energy source during strenuous physical activity (Lewis et al, 2010;Salway, 2012;Waśkiewicz et al, 2012). Furthermore, significant alterations to the tricarboxylic acid cycle intermediates were induced by a marathon (Turer et al, 2014) and could be attributed to additional strain placed on the electron transport chain (ETC), causing an imbalanced NADH:NAD + ratio (Esterhuizen et al, 2017). According to previous work (Stellingwerff, 2012), free glucose and other carbohydrate stores can become depleted within approximately 90 min after the start of the race, which most likely lead to the utilization of alternative fuel substrates (lipids and amino acids) for energy production (Waśkiewicz et al, 2012).…”

Emerging Insights into the Metabolic Alterations in Aging Using Metabolomics

“…The total number of primary metabolites in biological systems is currently debatable, although it was reported that yeast contains a few hundred metabolites [5], humans contain thousands of metabolites [6,7], whereas plants contain hundreds of thousands of metabolites [8,9]. The 'metabolome' represents the complete complement of small-molecule metabolites in a biological system [10,11], which varies in response to the genomic, transcriptomic, proteomic, or environmental alterations, and is based on the physiological, pathological, or developmental state of the biological system [12][13][14][15]. The metabolome is not directly involved in the "central dogma" information flow, unlike the genome, transcriptome, and proteome ( Figure 1), and indeed the human metabolome is much smaller than the proteome, which makes it relatively easier to characterize using the high-content and high-throughput system biology approaches [16].…”

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures

“…Interestingly, untargeted metabolomics profiling (Kennedy et al, ; Miller et al, ) performed on Patient 1 revealed elevated lactate, fumarate and glutarate, which indicate perturbation in energy metabolism secondary to mitochondrial dysfunction further providing functional evidence for the pathogenicity of the variant identified in COX4I1 . Evidence of mitochondrial dysfunction by the use of untargeted metabolomics analysis in CSF and plasma may provide functional validation for variants of unknown significance observed in nuclear genes associated with mitochondrial disease, providing semi‐quantitative values for TCA cycle intermediates and altered lipid metabolism as a consequence of abnormal mitochondrial function (Esterhuizen, Van Der Westhuizen, & Louw, ; Shayota et al, ; Tam et al, ).…”