Migraine in mitochondrial diseases and disorders: a bioenergetic perspective

Migraine is a neurological disorder increasingly recognized as involving systemic and neuronal bioenergetic vulnerability - a state marked by cellular energy disruption, impaired mitochondrial function, and reduced ATP-generating capacity. Accumulating evidence implicates mitochondrial dysfunction and impaired oxidative phosphorylation as contributors to migraine pathophysiology, linking cellular energy deficits to cortical spreading depression, trigeminovascular activation, and oxidative stress. These pathophysiological mechanisms and related channelopathies shape the cellular energetic landscape. Under these conditions, metabolic disturbances influence symptom variability and phenotype heterogeneity, although the directionality of these relationships reflects a dynamic, bidirectional feedback loop between bioenergetic stress and migraine pathobiology. Here, we describe mechanisms by which limited energetic reserve modulates migraine onset, symptom evolution, and recovery. We review phase-specific bioenergetic shifts across the migraine cycle and highlight how these core cellular processes modulate network excitability. In parallel, we summarize key biomarkers, including calcitonin gene-related peptide and growth differentiation factor 15, together with related salivary or oral-fluid assays, which assist in multi-compartment biological profiling. This pathobiological axis interfaces with localized molecular signaling cascades, including pituitary adenylate cyclase-activating polypeptide signaling, sirtuin biology, microRNA-based and epigenetic regulation, and gene-informed mechanisms. This progression underscores a growing interest in molecular pathways governing neuronal energy balance and in exploratory metabolic and mitochondrial-supportive compounds. Together, these observations offer a mechanistic overview of migraine as a disorder where metabolic homeostasis affects expression, severity, and recovery - a framework that may inform future biomarker research and mechanistically targeted interventions, particularly in individuals with primary mitochondrial disease.