Restoring Mitochondrial Function to Stop Degeneration

The link between the nociceptive muscular pain and weakness with mitochondrial function is tied with its capacity to produce energy in the form of ATP or converting substrate to other metabolites. Nevertheless, the metabolic pathways to achieve the formation of ATP are enzyme-dependent, and in turn, the enzymatic potential of these molecules depends on micronutrients derived from our diet. Therefore, it is easy to say that while the macronutrients will be metabolized to produce energy in the form of ATP, the micronutrients are the cofactors that make this possible. In short, restoring mitochondrial function through micronutrient supplementation encourages energy production, proper enzymatic function, and reduction of oxidative stress, resulting in pain reduction and improvement in muscle mass and movement ability.

Improving mitochondrial function in ICU patients.

The residual affectations of patients who underwent ICU intrahospital care put them in a critical situation where motor, neurological and sensory deficits are present. These deficits ultimately affect patients after several years of discharge; some of the repercussions are associated with muscle mass loss resulting in muscle weakness and pain and impaired pulmonary function. In addition, ICU survivors commonly suffer from social isolation due to symptoms like anxiety and depression, also linked to sexual dysfunction. 

Furthermore, several studies link the severity of motor function and muscle breakdown with the seriousness of the disease or organ failure that puts them under ICU care. A common finding among these patients is the inability to produce enough mitochondrial ATP, meaning an organelle dysfunction called bio-energetic failure.

Factors affecting mitochondrial function during and after critical illness.

Mitochondrial dysfunction, commonly observed by lower ATP production and increased lactate, is affected by many factors encountered during the critical illness window. Indeed, insulin resistance and hyperglycemia, gastrointestinal dysfunction, elevated oxidative stress, increased inflammatory and catabolic response are metabolic alterations leading to decreased mitochondrial function. In addition, bedridden patients have a higher risk of losing muscle mass and function. Furthermore, patients with assisted ventilation or severe gastrointestinal dysfunction have a reduced eating capacity and increased catabolic status, promoting muscle loss.

Micronutrients improving mitochondrial function

Micronutrients and trace minerals promote proper mitochondrial function by acting as enzymatic cofactors in energy metabolism or counteracting oxidative stress as antioxidants.

• Thiamin (vitamin B1): Thiamine functions as a cofactor of cytosolic transketolase and PDH. It also serves as an enzymatic cofactor for a-KGDH and branched-chain ketoacid dehydrogenase. A Thiamine deficiency affects the ability of pyruvate to enter the TCA cycle leading to increased lactic acid concentration and impaired metabolic aerobic metabolism.
• Riboflavin (vitamin B2): This vitamin plays an essential role as a building block for complexes I and II in the ETC and as a precursor of flavin adenine dinucleotide (FAD)and flavin mononucleotide (FMN), which are molecules that store ATP for later use. A deficient dietary intake of riboflavin results in impaired mitochondrial oxidation of fatty acids and branched amino acids due to the inhibition of FAD-dependent dehydrogenase.
• Niacin (vitamin B3): Niacin is the precursor of ATP storing molecules nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Low levels of niacin are associated with an overall decreased energy production due to its involvement in glycolysis, TCA, ETC metabolic pathways.
• Pantothenic acid (vitamin B5): Proper concentration of vitamin B5 is essential for energy production from fatty acids. Without pantothenic acid, proper levels of CoA are not attainable, affecting the function of PDH and α-KGDH.
• Biotin (vitamin B7): Biotin is used as a coenzyme of 5 major mitochondrial carboxylases; without fatty acid oxidation and gluconeogenesis are impaired.
• Folate (vitamin B9): Folate serves as serine cleavage to 5,10-methyltetrahydrofolate; without it, the ATP production is decreased, and DNA formation is severely affected.
• Ascorbic acid (vitamin C): Involved in the biosynthesis of carnitine, the critical factor in beta-oxidation. Impaired beta-oxidation, impaired ATP production is attributed to its deficiency. Vitamin C is considered an antioxidant.

The mitochondrial structure is critical for its function. without it, none of the metabolic pathways would work and this would directly affect our capacity to produce energy. Critical illness always leaves remnants of secondary deficits, most of them directly associated with mitochondrial health. Furthermore, physical factors that affect nutrient supply, such as assisted ventilation, chewing or swallowing issues associated with the illness will determine the volume and quality of the dietary intake. In addition, this last issue is accompanied by elevated oxidative stress and catabolic response, increasing energy requirements that cannot be met due to the aforementioned physiological issues. Consequently, this nutrient deficiency will continue to affect mitochondrial potential and eventually affect muscle mass,  strength, the nociceptive pain sensation due to higher levels of lactate and pyruvate in the cytosol.  Recent studies report that the only way to counteract this mechanism is to provide micronutrient supplementation, some of them recommend doing this in higher doses. – Ana Paola Rodriguez Arciniega, MS

References:

Wesselink, E et al. “Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence.” Clinical nutrition (Edinburgh, Scotland) vol. 38,3 (2019): 982-995. doi:10.1016/j.clnu.2018.08.032

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