Why Your Brain Fog Won't Lift: The Six Mechanisms of Cognitive Dysfunction in Chronic Illness, and Why Standard Interventions Keep Failing — Mechanism Three: Mitochondrial Bioenergetic Failure in the Brain

The brain is the most metabolically demanding organ in the body. It accounts for roughly two percent of body mass and twenty percent of resting energy expenditure. The cells responsible for this consumption are primarily neurons, which require continuous ATP for ion pump activity (maintaining the resting membrane potential consumes a substantial fraction of total neural energy), synaptic vesicle recycling, neurotransmitter synthesis and packaging, axonal transport, and the maintenance of the elaborate cellular architecture that distinguishes neurons from less specialized cells. When mitochondrial throughput is compromised, neurons feel it first. Several mechanisms operate. The NAD pool, which is critical for sirtuin function and for substrate level signaling in the matrix, can be depleted by CD38 upregulation in chronic inflammation, by PARP activation in oxidative stress, and by direct viral effects on NAD handling in post viral syndromes. The electron transport chain itself can be compromised by iron sulfur cluster assembly defects, by direct viral effects on complex I or complex IV, by chronic exposure to oxidative damage, or by substrate limitation. The phosphocreatine reserve that buffers acute ATP demand can be reduced, which limits the brain's capacity to handle cognitive load spikes. The recent literature on long COVID and ME/CFS has produced direct evidence for mitocho