Currently, there isn’t an established ODX pattern of biomarkers designed for evaluating mitochondrial dysfunction using commonly available biomarkers. However, there are some biomarkers that can be investigated further for issues tied to mitochondrial dysfunction, including pH dysregulation, tissue oxygenation issues, and the Warburg effect.
Many readily available blood biomarkers are associated with pH, oxygenation, and oxidative stress that can affect mitochondrial function. These include:
The pH of the blood is ideally maintained within a tight range of 7.35-7.45 (Brinkman 2022), and excursions away from optimal should be quickly corrected. The presence of metabolic acidosis or alkalosis can be evaluated by measuring serum bicarbonate and anion gap. A decrease in serum bicarbonate reflects metabolic acidosis, while increased bicarbonate reflects metabolic alkalosis (ODX Bicarbonate, 2022). An increased anion gap reflects metabolic acidosis, while a decreased anion gap is associated with metabolic alkalosis (ODX Anion Gap, 2022).
Red blood cells are key to optimal oxygenation as they carry oxygen bound to hemoglobin and deliver it to cells and tissues throughout the body. Therefore, oxygen delivery will be compromised when RBCs or hemoglobin are depleted, and anemia is persistent (Da Silva 2021). Oxygenation can also be compromised with increased hemoglobin A1C and lipid peroxidation (Demir 2001).
Additional blood biomarker changes that can affect oxygenation include (Pagana 2021):
The Warburg effect is the phenomenon that occurs when cancer cells preferentially use the pathway of glycolysis, instead of aerobic pathways, to metabolize glucose even in the presence of adequate oxygen. The end product of glycolysis is lactate, formed via the action of lactate dehydrogenase (LDH) on pyruvate (Liu 2021). More specifically, it is the isoenzyme LDH5 responsible for the anaerobic conversion of pyruvate to lactate (Koukourakis 2019).
Although glycolysis usually occurs when oxygen is in short supply, the “aerobic glycolysis” and impairment of oxidative phosphorylation that characterize the Warburg effect reflect mitochondrial dysfunction and increase malignancy and tumor progression (Pascale 2020). The oxidative stress that occurs because of aerobic glycolysis and mitochondrial dysfunction also supports cancer cell mutagenesis and the progression of tumor development (Sotgia 2011).
However, oxidative stress itself can promote mitochondrial dysfunction in a vicious cycle.
Unmitigated oxidative stress can induce mitochondrial dysfunction. Biomarker assessment of oxidative stress should include ascorbic acid, alpha-tocopherol, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GR), and lipid peroxidation (Bouzid 2014).
Elevated methylmalonic acid (MMA), primarily caused by vitamin B12 insufficiency or functional deficiency, is considered a biomarker of oxidative stress and mitochondrial dysfunction as well. Vitamin B12 is required for the conversion of methylmalonic-CoA to succinyl-CoA in the mitochondria. Succinyl-CoA then enters the tricarboxylic acid cycle, facilitating the production of energy from fatty acids and proteins. Oxidative stress can disrupt vitamin B12 activity, resulting in decreased mitochondrial energy generation and an increase in serum MMA (Polytarchou 2020).
Additional biomarker changes associated with oxidative stress and potentially with mitochondrial dysfunction include (ODX Oxidative Stress, 2020):
Biomarkers associated with mitochondrial dysfunction observed in 41 male children with autism spectrum disorder (ASD) include significant increases in LDH, pyruvate, creatine kinase, and CoQ10. Melatonin levels were above the cut-off, and glutathione was below the cut-off in 62% and 81% of ASD individuals, respectively. Although significant lactate, AST, and ALT elevations were previously observed in ASD individuals, differences in these biomarkers were not significant in the present study (Khemakhem 2017).
Mitochondrial dysfunction clearly underlies mitochondrial dysfunction disorders but may also play a role in Alzheimer’s disease, Parkinson’s disease, and glaucoma. Although a single blood biomarker with 100% sensitivity has not been identified, elevated lactate has a sensitivity of 73.5% in individuals with mitochondrial dysfunction. The sensitivity of elevated lactate as a biomarker of mitochondrial dysfunction can be increased by establishing baseline levels and comparing those to levels under various conditions such as stages of exercise and recovery and meal timing, e.g., fasting, before meals, and after meals. Elevated pyruvate may be present with mitochondrial dysfunction and should be assessed under conditions similar to those applied to lactate testing.
Elevations in creatine and creatinine kinase may be seen with mitochondrial dysfunction. However, they can also be seen with muscular dystrophy and inflammatory disorders and have a low sensitivity for determining mitochondrial function. Production of alanine, glycine, proline, and threonine are increased with mitochondrial dysfunction, while arginine may be decreased. Supplemental arginine is used therapeutically in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). However, altered amino acid patterns are not exclusive to mitochondrial dysfunction and can change under stress and exercise.
Advanced mitochondrial diseases should be further assessed using tissue biopsy, including oxidative phosphorylation (OXPHOS) evaluation. Mitochondrial membrane potential can be measured in advanced clinical settings. Genetic variants in mitochondrial DNA can be detected in white blood cells and can help evaluate mitochondrial dysfunction. Acquired mutations can be caused by prolonged exposure to oxidative damage, deficiencies in DNA repair mechanisms, asymmetrical replication, and drugs.
Note that a TSH above optimal may also be associated with mitochondrial dysfunction and should be evaluated and monitored closely (Raymond 2021).
Assessment of mitochondrial function may include evaluation of
Common sources of oxidative stress should be identified:
Mitochondrial dysfunction may play a role in
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ODX Research Blog. Electrolyte Biomarkers: Bicarbonate, CO2. June 3, 2022. https://www.optimaldx.com/research-blog/electrolyte-biomarkers-bicarbonate-co2
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