This figure depicts shared pathways in the illnesses described in this paper that may cause secondary fatigue. Activation of Toll-like receptors 2/4 (TLR2/4) by pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) leads to the production of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 together with elevated levels of reactive oxygen and nitrogen species (ROS/RNS). IL-1β is a primary source of secondary fatigue and together with the other cytokines acts as a secondary source of fatigue via the inhibition of mitochondrial performance and the provocation of metabolic dysfunction in the brain via the activation of astrocytes and microglia. ROS/RNS can also be a primary cause of secondary fatigue by damaging lipids and proteins which are essential for the performance of mitochondria and inhibiting the electron transport chain. These actions lead to impaired mitochondrial performance which is also a source of fatigue in a similar manner as found in syndromic mitochondrial diseases. This figure is original.