Neuronal fatty acid bioenergetics: An emerging pathway and potential point in convergence in hereditary spastic paraplegias.

The human brain is an energetically demanding organ. Neurons have traditionally been considered to rely predominantly on glucose to sustain neuronal activity under normal physiological conditions. However, recent advances challenge this long-standing view, demonstrating that neurons can oxidise endogenous and exogenous long-chain fatty acids through mitochondrial β-oxidation to create energy. In this mini-review, we discuss the emerging role of neuronal fatty acid β-oxidation and how fatty acid metabolism is integrated with glycolysis, lipid storages, and mitochondrial energy production. We further explore the ER-lipid droplet-mitochondria nexus as a metabolic hub coordinating fatty acid mobilisation, storage, and oxidation, and investigate how abnormalities in these organelles and their inter-organelle coupling converge across hereditary spastic paraplegia subtypes to disrupt neuronal lipid metabolism and mitochondrial bioenergetics. Finally, we discuss how these emerging mechanisms may reveal new therapeutic opportunities for hereditary spastic paraplegias.