Mamm Genome. 2026 Sep 18. pii: 108. [Epub ahead of print]37(1):
Mitochondria are essential organelles responsible for cellular energy production and the regulation of key metabolic and signalling pathways. Their function depends on the coordinated expression of both mitochondrial and nuclear genomes, and mitochondrial dysfunction leads to a diverse group of mitochondrial diseases. The nervous system is particularly vulnerable to mitochondrial dysfunction due to the high energetic demands and complex morphology of neurons. Neurons rely heavily on mitochondrial ATP production to support processes such as synaptic transmission, axonal transport, and calcium homeostasis, which are tightly regulated by mitochondrial dynamics, intracellular trafficking, and quality control mechanisms. In mitochondrial diseases, impairment of these processes contributes to a range of neurological manifestations, including epilepsy, stroke-like episodes, Leigh syndrome, ataxia, and peripheral neuropathy. Despite the ubiquitous presence of mitochondria, neuronal vulnerability varies between distinct neuronal populations, reflecting differences in neuronal morphology and metabolic demands. This review summarises key mechanisms underlying neuronal susceptibility in mitochondrial disease and highlights how defects in mitochondrial bioenergetics, dynamics, and transport contribute to characteristic neurological phenotypes. Understanding these mechanisms may provide insights into tissue-specific vulnerability and identify potential therapeutic targets to treat mitochondrial diseases and other neurodegenerative disorders associated with mitochondrial mechanisms.