Fatty Acid Oxidation Disorders and Mitochondrial Dysfunction

Fatty acid oxidation (FAO) disorders are inherited defects in the mitochondrial pathway that converts long-chain fatty acids into energy, leading to impaired ATP production during fasting or physiological stress. Accumulation of partially oxidised acyl intermediates can disrupt mitochondrial bioenergetics, redox balance and calcium homeostasis, precipitating hypoketotic hypoglycaemia, cardiomyopathy and skeletal myopathy. Emerging evidence reveals bidirectional interplay between FAO and oxidative phosphorylation, whereby primary FAO enzyme deficiencies can destabilise respiratory supercomplexes and, conversely, defects in the electron transport chain may impair β-oxidation. Genetic variants affecting enzymes such as medium- and long-chain acyl-CoA dehydrogenases and subunits of the mitochondrial trifunctional protein give rise to a spectrum of clinical phenotypes. Advances in newborn screening, dietary management, metabolic imaging and animal models have deepened understanding of pathophysiology, while novel therapies aim to bypass metabolic blocks and reduce toxic intermediate accumulation. This intricate link between lipid metabolism and mitochondrial function holds implications not only for rare inborn errors but also for common conditions of metabolic stress.

Research from Nature Portfolio

A genetically precise knock-in mouse carrying the human pathogenic G1528C variant in the HADHA gene faithfully reproduces the clinical spectrum of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Homozygous animals exhibit reduced fat oxidation, hypoketotic hypoglycaemia during fasting, exercise intolerance, dilated cardiomyopathy and retinal dysfunction, mirroring human manifestations. Metabolic profiling demonstrated elevated 3-hydroxyacylcarnitines and diminished ketone production, while exercise and wire-hang tests quantified neuromuscular deficits. This model offers a robust platform for mechanistic studies of mitochondrial respiratory dysfunction and preclinical evaluation of targeted therapies.

Fatty Acid Oxidation Disorders and Mitochondrial Dysfunction publication trend

The graph below shows the total number of articles in fatty acid oxidation disorders and mitochondrial dysfunction across all publications each year (not limited to Nature Index journals).

Technical terms

Fatty acid oxidation (FAO): metabolic process that breaks down fatty acids into acetyl-CoA within mitochondria to generate energy.

Oxidative phosphorylation (OXPHOS): mitochondrial mechanism producing ATP through an electron transport chain and proton gradient.

Respiratory supercomplexes: assemblages of respiratory chain complexes that enhance efficiency of electron transfer.

Carnitine shuttle: system of enzymes and transport proteins that translocate long-chain fatty acids into mitochondria for β-oxidation.

Triheptanoin: odd-chain triglyceride used therapeutically to supply anaplerotic substrates to the tricarboxylic acid cycle in FAO disorders.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD): inherited defect in the HADHA subunit of the trifunctional protein leading to impaired oxidation of long-chain fatty acids and multisystem pathology.

References

1. HADHA Regulates Respiratory Complex Assembly and Couples FAO and OXPHOS. Advanced Science (2024).
2. A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Communications Biology (2023).
3. Nutritional Management of Patients with Fatty Acid Oxidation Disorders. Nutrients (2024).
4. Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Reviews in Endocrine and Metabolic Disorders (2018).