To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. •Comprehensive computational model of motor neuron•Model representation of vulnerable and resistant motor neurons to ALS•Shortage in ATP causes deadly alterations in both Na+/K+ and Ca++ homeostasis•Localized ATP deficit triggers ion dyshomeostasis and fasciculation-like spikes Results from a computational model by Le Masson et al. suggest that ATP deficits can cause potentially deadly ion disregulation, particularly in ALS-vulnerable motor neurons. Modest bioenergetics defects in the model account for a number of salient features of this paralytic disorder.