Post-exertional malaise (PEM) is a common core symptom in various chronic debilitating conditions, such as Post COVID-19 Condition (PCC, also known as Long COVID) and Chronic Fatigue Syndrome (CFS). It is characterized by the delayed and persistent exacerbation of symptoms following even mild physical or cognitive activities. This review presents a systematic review of the pathophysiological mechanisms involved in PEM, proposing a dynamic framework of multi-system interactions that may lead to homeostatic imbalance. The etiology of PEM is multifactorial, potentially involving factors such as the persistent presence of pathogens, exposure to environmental toxins, and genetic predisposition. Collectively, these factors may establish a vulnerable baseline that heightens the body's physiological response to stressors, such as exercise, potentially triggering a pathological reaction. First, mitochondrial dysfunction and metabolic abnormalities may act as potential initiating factors in PEM, manifesting as impaired ATP synthesis, overproduction of reactive oxygen species (ROS), and the accumulation of metabolic byproducts. It is crucial to emphasize that exercise itself induces a 'toxic excitatory effect,' whereby healthy individuals enhance mitochondrial function and antioxidant defenses through physical activity. However, in individuals predisposed to PEM, due to underlying pathological conditions (e.g., sequelae of viral infections), this adaptive process is disrupted, preventing effective restoration of mitochondrial homeostasis and may initiate a potential vicious cycle of dysfunction. Second, ROS and mitochondrial DNA (mtDNA), as damage-associated molecular patterns (DAMPs), along with pathogen-associated molecular patterns (PAMPs), may activate the NLRP3 inflammasome and induce the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, potentially transforming localized metabolic stress into a systemic inflammatory response. Subsequently, peripheral inflammation may be transmitted to the central nervous system through disruption of the blood-brain barrier and vagal nerve pathways, activating glial cells and initiating neuroinflammation. This process may ultimately affect the brain's interoceptive network, particularly the insular cortex, resulting in altered perception and processing of signals related to fatigue and pain. Furthermore, mitochondrial dysfunction in neurons may contribute to central energy depletion, which may impair synaptic plasticity and induce cognitive deficits and brain fatigue. Ultimately, this review proposes that PEM may arise from a complex interplay among mitochondrial dysfunction, immune activation, and neuroinflammation, which together form a self-perpetuating loop of "energy exhaustion - inflammation amplification," potentially contributing to the chronic and multi-system nature of PEM symptoms. The integrated "metabolism-immune-neuro" interaction model presented in this article may provide a potential comprehensive framework for understanding PEM and highlights the need for a multi-target, collaborative intervention approach that may help disrupt the pathological cycle.
