Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases

Central nervous system (CNS) diseases, both traumatic and neurodegenerative, are characterized by impaired mitochondrial bioenergetics and often disturbed mitochondrial dynamics. The dysregulation observed in these pathologies leads to defective respiratory chain function and reduced ATP production, thereby promoting neuronal death. As such, attenuation of mitochondrial dysfunction through induction of mitochondrial biogenesis (MB) is a promising, though still underexplored, therapeutic strategy. MB is a multifaceted process involving the integration of highly regulated transcriptional events, lipid membrane and protein synthesis/assembly and replication of mtDNA. Several nuclear transcription factors promote the expression of genes involved in oxidative phosphorylation, mitochondrial import and export systems, antioxidant defense and mitochondrial gene transcription. Of these, the nuclear-encoded peroxisome proliferator-activated receptor. coactivator 1 alpha (PGC-1 alpha) is the most commonly studied and is widely accepted as the 'master regulator' of MB. Several recent preclinical studies document that reestablishment of mitochondrial homeostasis through increased MB results in inhibited injury progression and increased functional recovery. This perspective will briefly review the role of mitochondrial dysfunction in the propagation of CNS diseases, while also describing current research strategies that mediate mitochondrial dysfunction and compounds that induce MB for the treatment of acute and chronic neuropathologies.