PublicationDysfunctions of Mitochondrial Fatty Acid β-oxidation in Rare and Common Diseases

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Certain abnormalities in mitochondrial β-oxidation of fatty acids (β-OAG) appear to play a major role in the pathogenesis of several common diseases (diabetes, obesity, heart disease). Genetic deficiencies affecting β-OAG also underlie a range of rare diseases with highly variable phenotypes, from fatal cardiohepatic failure in infants to myopathies in adults. These different pathologies reveal the key role of β-OAG in several organs with high ATP requirements (heart, muscle, liver, kidney). Recent data suggest that β-OAG may also participate in other complex functions (chromatin modifications, control of stem cell activity, cancer cell fate). A delicate balance exists between the use of fatty acids and glucose as a source of metabolic energy. Depending on the organ in question, this balance can be shifted to varying degrees in response to physiological or pathophysiological changes: this is referred to as metabolic flexibility [2, 3]. Generally speaking, it is accepted that fatty acid utilization plays a predominant role in all situations requiring restriction of glucose use, such as fasting or physical exercise. Under these conditions, lipolysis of adipose tissue significantly increases circulating levels of long-chain fatty acids and, consequently, their mitochondrial β-oxidation in many tissues. These energy functions of β-FAO are modulated by a set of nutritional and hormonal factors that act through different molecular, allosteric, transcriptional, and post-translational mechanisms via a complex cellular and nuclear signaling network, which allows for adjustment of the activity of this metabolic pathway in response to different physiological or pathophysiological contexts [4-7]. Genetic defects affecting β-OAG, with their complex array of clinical manifestations, reveal the importance of this metabolic pathway in the physiology of many organs. Other β-OAG dysfunctions are involved in the pathogenesis of various common diseases, including diabetes [8], obesity [9], and heart disease [10]. Beyond classical energy production mechanisms, recent data collected in different models suggest the involvement of β-OAG in functions that have long remained unsuspected. β-OAG could thus participate in epigenetic modifications of chromatin [11] and in the differentiation of neuronal stem cells. Mitochondrial β-oxidation of fatty acids (β-OAG) plays a major role in the supply of ATP to many organs or tissues with high energy demands, such as the heart, skeletal muscles, liver, and kidneys. The basic principle of this metabolic pathway (Figure 1) relies on a recurring sequence of four enzymatic reactions (called the Lynen helix) (Figure 2) that convert fatty acids into acetyl-CoA. This is then incorporated into the Krebs cycle to complete oxidation. This entire process generates large quantities of NADH (reduced nicotinamide adenine dinucleotide) and FADH2 (reduced flavin adenine dinucleotide), which, by supplying electrons to the mitochondrial respiratory chain, enable the production of ATP with a high energy yield. In both humans and rodents, β-OAG primarily uses long-chain fatty acids (16- and 18-carbon) that are abundant in the adult diet or stored in adipose tissue reserves [1]. In many tissues (heart, muscle, liver, etc.), there is a Vignette permanently present (Photo © Inserm-Barelli, Hélène).