Targeting mitochondrial dysfunction across the lifespan. Role of bezafibrate in neurodevelopment and neurodegeneration

Neurodevelopmental and neurodegenerative disorders have traditionally been viewed as distinct clinical entities, separated by age of onset and trajectory. However, emerging evidence suggests they represent different temporal phases of a continuous neurological spectrum. A central, shared mechanistic hub in this continuum is mitochondrial dysfunction, which impairs the formation and maintenance of neuronal and glial networks, delaying early maturation and heightening vulnerability to later-life decline. This perspective highlights the critical role of mitochondrial health, particularly within astrocytes, in maintaining synaptic homeostasis and network stability. Consequently, targeting mitochondrial pathways offers a promising cross-cutting therapeutic strategy. Specifically, bezafibrate, a pan-PPAR agonist commonly used for dyslipidemia, has demonstrated significant efficacy in restoring mitochondrial biogenesis and resilience via the PGC-1α pathway. Across various in vitro and in vivo models—including tauopathy-associated cortical and retinal organoids, as well as 22q11.2 deletion syndrome models—bezafibrate successfully rescues early neurodevelopmental delays (improving neuronal, synaptic, and glial maturation) and mitigates late-stage neurodegenerative phenotypes (reducing neurodegeneration, neuroinflammation, and protein aggregation). By bridging physiological and pharmacological pathways governing mitochondrial health, bezafibrate represents a robust therapeutic candidate for preserving brain function from early development through aging.