Mitochondrial fatty acid β-oxidation disorders (FAODs) are a group of approximately 20 inherited diseases resulting from genetic mutations that codify enzymes or proteins involved in mitochondrial β-oxidation and fatty acid transport. FAODs have a combined incidence of about 1:9000 and are fairly common inborn errors of metabolism.
When glycogen is absent, FAO becomes a vital source of energy production. Fatty acids are therefore particularly necessary in catabolic states, such as during intense exercise or prolonged fasting. Patients with a FAOD typically present with medical injuries caused by the prolonged lack of energy, such as cardiomyopathy, hepatopathy, neuropathy, myopathy, as well as biochemical disorders, such as hypoketotic hypoglycemia, hyperammonemia, and hypotony.
Among the 20 known FAODs, 6 can be further grouped into long chain fatty acid oxidation disorders (LCFAODs). Other examples of FAODs are of the medium chain and the very long chain varieties. Despite their different classifications, all of these FAODs share a similar pathophysiology relating to how energy is synthesized in the body. The pathophysiology of FAODs, particularly as they relate to the mechanisms underlying neurological damage, is poorly understood.
It is the common pathophysiological features of FAODs and the mechanisms underlying them that are the subject of a study published in Cellular and Molecular Biology. Researchers set out to review the latest scientific literature on the role of oxidative imbalance and mitochondrial dysfunction in the most common FAODs, including LCFAODs. For the purpose of this article, we will be looking specifically at their findings as they relate to LCFAOD.
Oxidative Disbalance and Mitochondrial Dysfunction
The available scientific literature tells us that LCFAODs have a worldwide prevalence of 1:250,000 in newborns. LCFAOD is inherited in an autosomal recessive manner and has a heterogeneous clinical presentation. In neonates, severe disease — typically characterized by cardiopathy, hepatopathy, hypoketotic hypoglycemia, and lactic acidemia — usually results in death shortly after. Patients who present later typically have milder symptoms, such as hypotonia, seizures, retinopathy, cardiomyopathy, and peripheral neuropathy.
The common therapeutic approach to LCFAODs is similar to that of other FAODs. This includes advising patients against fasting, urging precautions against acquiring acute infections, and restricting fatty acids in the diet, as well as taking supplements of carbohydrate and medium-chain triacylglycerols (MCTs). However, even early implementation of these steps may not be enough to prevent symptomology in many young LCFAOD patients. A better understanding of the pathophysiology of the disease will help us explore new targeted therapies that may improve patients’ quality of life.
A key to deepening our understanding of LCFAOD is to better comprehend the mechanisms underlying tissue damage in LCFAOD. Researchers have observed lactic acidemia, mitochondrial morphological abnormalities, and the blocking of respiratory chain complexes in LCFAOD patients. This suggests that mitochondrial dysfunction is intricately involved in the pathogenesis of the disease.
This is further strengthened by in vitro studies showing that major accumulated metabolites in LCFAOD, 3-hydroxytetradecanoic (3HTA) and 3-hydroxypalmitic(3HPA) acids, significantly increase resting respiration and decrease adenosine diphosphate (ADP)-stimulated respiration. In addition, these metabolites uncouple respiration in the mitochondria, diminish mitochondrial membrane potential, and decrease calcium retention capacity in calcium-loaded mitochondria from the skeletal muscle, liver, and heart of experimental rats. These fatty acids were also observed to cause a significant decrease in ATP production, which in turn leads to severe energy dysfunction.
In addition, 3HTA-induced mitochondrial alterations in the heart were completely blocked by mitochondrial permeability transition (mPT) inhibitors and ruthenium red (a calcium uptake blocker). This shows that the opening of the calcium-dependent mPT pore is associated with the observed effects of LCFAOD.
Previous studies have shown that oxidative stress and oxidative phosphorylation uncouplers may open the mPT pore in calcium-loaded mitochondria. More recent studies from urine samples of LCFAOD patients reflect lipid and DNA oxidation damage, which probably indicates higher production of nitrogen and oxygen reactive species.
Taken together, these studies show that mitochondrial dysfunction and oxidative imbalance are important mechanisms that contribute to LCFAOD. This, in turn, “can contribute, at least in part, to the cardiac, hepatic, and muscular alterations manifested by the patients,” wrote the authors of this study.
Looking Toward Prevention
This review of the scientific literature available around FAODs, including from both patient and animal studies, demonstrates how mitochondrial dysfunction and oxidative imbalance play a crucial role in causing the classic signs and symptoms of this disease.
Much of the therapeutic options available in LCFAODs and other FOADs are focused on minimizing the clinical manifestations of the disease. As we deepen our understanding of the pathophysiology of metabolic diseases like FOADs, medicine may soon pivot to targeting their genetic causes instead. It would represent a massive step forward if we can redirect our attention from the therapeutic management of symptoms of this disease to its outright prevention in the first place. With continued research, we may get there sooner than we think.
References
Ribas GS, Vargas CR. Evidence that oxidative disbalance and mitochondrial dysfunction are involved in the pathophysiology of fatty acid oxidation disorders. Cell Mol Neurobiol. Published online September 2, 2020. doi:10.1007/s10571-020-00955-7
Exil VJ, Gardner C, Rottman J, et al. Abnormal mitochondrial bioenergetics and heart rate dysfunction in mice lacking very-long-chain acyl-CoA dehydrogenase. Am J Physiol Heart Circ Physiol. 2006;290(3):H1289–H1297. doi:10.1152/ajpheart.00811.2005
