Mitochondrial Crossroads in Neurobiology: From Cellular Vulnerability to Therapeutic Opportunity

Abstract

Mitochondria integrate metabolic, signalling, and quality-control pathways that are critical for neuronal and glial homeostasis. Beyond ATP production, they regulate redox balance, calcium dynamics, proteostasis, innate immune signalling, and the molecular pathways governing cell survival and death. This Closing Editorial synthesizes the main advances reported in this Collection across neurodegeneration, neurodevelopmental vulnerability, inherited mitochondrial disorders, neurotrauma, drug-induced neurotoxicity, and neuroimmune regulation. Collectively, these studies establish mitochondrial dysfunction as a heterogeneous and context-dependent process rather than a uniform or secondary consequence of neurological disease. Mitochondrial alterations are dynamically regulated across cell types, subcellular compartments, and disease stages, and are tightly coupled to inter-organelle communication and cellular stress-response pathways. The contributions highlight convergent mechanisms linking astrocytic mitochondrial DNA damage, dysregulated RNA-binding proteins, altered mitochondria–endoplasmic reticulum contacts, disrupted iron and redox homeostasis, and mitochondrial–inflammatory signalling to neuronal vulnerability and impaired circuit integrity. They also identify potential therapeutic targets while defining key unresolved questions, particularly the need to establish mechanistic causality, delineate cell- and compartment-specific mitochondrial responses, and validate findings using clinically relevant models and outcome measures. Overall, this Collection positions mitochondrial biology as a mechanistic framework connecting metabolic dysfunction, cellular stress, neuroinflammation, and neuronal degeneration, and supports its development as a therapeutic target for disease-modifying interventions in neurological disorders.