Mitochondria are the key organelle responsible for cellular energy product.
Dyfunction of these organelles can result in excess fatigue and other symptoms commonly encountered in almost every chronic disease.
Mitochondrial dysfunction, characterized by a loss of efficiency in the electron transport chain and reduction of synthesis of ATP, is a characteristic of aging and essentially all chronic diseases, including neurodegenerative diseases, cardiovascular diseases, diabetes and metabolic syndrome, autoimmune diseases, neurobehavioral and psychiatric diseases, gastrointestinal diseases, musculoskeletal diseases, cancer, and chronic infections.
Mitochondrial dysfunction can come about due to not having enough mitochondria, not having the needed materials for the mitochondria to adequately do its job, or from a dysfunction in the electron transport and ATP-generating processes. Number and functional status can be altered by (1) combining partially dysfunctional mitochondria using their undamaged parts to improve overall function, (2) creating completely new mitochondria, and (3) removing damaged mitochondria. These processes are controlled by complex systems that sense deterioration of the organelles.
The ability of cells to produce high-energy molecules, like ATP, is related to the ability of mitochondria to convert energy of metabolites to NADH and transfer electrons from NADH to the electron transport chain. This creates a proton gradient between the inner and outer mitochondrial membranes and an electrochemical gradient across the inner membrane. These gradients help drive the process that creates high-energy potential ATP from lower-energy ADP.
A byproduct of the electron transport chain are reactive oxygen species (ROS). These are highly reactive free radicals that can damage proteins, and even DNA. The good news is that some mechanisms can neutralize these free radicals, such as dismutase enzymes and antioxidants.
Another reaction of the electron transport chain can induce uncoupling proteins which can result in protons leaking back across the proton gradient, thus reducing ATP production. This leak also consume oxygen and can result in ROS production leading to the damage described earlier.
Normally, antioxidant systems prevent excessive amounts of oxidation to cellular molecules. Endogenous defenses are mediated by glutathione peroxidase, catalase, and superoxide dismutase among other enzymes. Some dietary antioxidants can also affect antioxidant status.
Mitochondrial dysfunction is related to excess fatigue – perceived as a loss of overall energy and an inability to perform even simple tasks without exertion. Mild fatigue may be the result of any number of conditions, such as depression or psychological conditions. Severe fatigue is more likely to involve cellular energy systems due to loss of mitochondria function and reduced ATP production.
Oxidative damage to the mitochondrial membranes impairs function. Individuals with chronic fatigue syndrome often present with evidence of oxidative damage to DNA and cellular lipids.
Many natural supplements have been used to treat non-psychological fatigue and mitochondrial dysfunction, including vitamins, minerals, antioxidants, metabolites, enzyme inhibitors and cofactors, mitochondrial transporters, herbs, and membrane phospholipids. However, few are actually considered effective…
Alpha-Lipoic Acid (ALA)
ALA has been used clinically as an oral supplement in the treatment of complications associated with diabetes, such as neuropathies, inflammation, and vascular health. This has been attributed mainly to effects on gene regulation and glucose uptake and metabolism as well as antioxidant effects.
Given as an oral supplement, ALA is rarely present in tissues above micromolar levels and so is unlikely to be directly involved as an antioxidant. However, its ability to increase glutathione levels is an important antioxidant property.
ALA can also remove excess copper, iron, and other metals as a transition metal chelator, important in mitigation of heavy metal poisoning. This may help improve cognitive and mitochondrial functions. It is generally considered as safe to support mitochondrial function and reduce oxidative stress (200-600 mg/day).
L-carnitine is a fatty acid transporter found in all mammals. It is involved in the transport of fatty acids into the mitochondria for beta-oxidation and also helps removal excess acyl groups from the body and in intracellular coenzyme A (CoA) homeostasis. L-carnitine is usually maintained within narrow concentration limits, so dietary supplementation is important to maintain optimal concentrations within cells. L-carnitine deficiency disorders are associated with reduced mitochondrial function, insulin resistance, and coronary artery disease.
L-carnitine supplementation has been advertised to potentially improve physical performance – the rationale being that increased use of fat as the main energy source during extreme exercise should reduce the need for carbohydrates. The body can store more energy as fat than as carbohydrate (glycogen) so a greater reliance on fat than carbohydrates for energy should, in theory, increase overall energy production and reduce exercise-induced fatigue.
While studies on physical performance have not produced promising results, its use in clinical disorders characterized by low L-carnitine concentrations or impaired fatty acid oxidation – such as diabetes, sepsis, and renal disease – have been successful. Other trails on alcoholism, hepatic encephalopathy, coronary heart diseases, cerebral ischemia, and infertility have shown positive effects on the signs and symptoms of these conditions
Coenzyme Q10 (CoQ10)
Also known as ubiquinone, CoQ10 is a key component of the electron transport chain and a widely used natural supplement. Clinically, CoQ10 has ben used to reduce symptoms and progression of various neurodegenerative diseases, like Alzheimer’s, Huntington’s, and Parkinson’s diseases.
Nicotinamide Adenine Dinucleotide (NADH)
NADH is involved in over 200 cellular reactions. Human beings require NADH and a deficiency results in a condition called pellagra – characterized by the 4 D’s: dermatitis, diarrhea, dementia, and (eventually) death.
The usual route of supplementation is via NADH precursors, such as niacin, nicotinic acid, or nicotinamide. However, recently, oral NADH supplements have been stabilized and developed that can be directly taken and absorbed in the GI system.
Dietary replacement of mitochondrial membrane phospholipids (lipid replacement therapy) using food-derived molecules has proven effective at increasing mitochondrial function and reducing fatigue. The use of oral membrane phospholipids + antioxidants (500-2000 mg/day) has been effective in the treatment of certain clinical conditions, such as fibromyalgia and chronic fatigue syndrome.
Loss of mitochondrial function occurs due to: (1) loss of maintenance of the electrical and chemical transmembrane potential of the inner mitochondrial membrane, (2) alterations of the function of the electron transport chain, or (3) reduction in transport of critical metabolites into the organelle. These changes may result in a reduced efficiency of oxidative phosphorylation and subsequent production of ATP.
Clinical trials have shown benefit in using supplements such as L-carnitine, alpha-lipoic acid (ALA), microencapsulated NADH, membrane phospholipids, and other nutrients. Use of these supplements may reduce fatigue and other symptoms associated with chronic disease and can naturally restore mitochondrial function, helping restore quality of life.