Pituitary adenylate cyclase-activating polypeptide and mitochondrial homeostasis in neuronal injury: mechanisms and translational prospects.

Pituitary adenylate cyclase-activating peptide (PACAP) is a pleiotropic neuropeptide widely distributed in the nervous system, exhibiting potent cytoprotective effects across a spectrum of neurological disorders. Its neuroprotection is largely mediated through three G protein-coupled receptors (PAC1, VPAC1, VPAC2), activating downstream pathways that converge on preserving mitochondrial integrity. Mitochondrial dysfunction, characterized by bioenergetic failure, oxidative stress, perturbed dynamics (such as fusion and fission), and impaired quality control, is a hallmark of traumatic nerve injury, cerebral ischemia, and retinal neuropathy. This review systematically synthesizes recent evidence elucidating how PACAP counteracts these pathological processes. We detail its mechanisms in 1) mitigating neuropathic pain and promoting axonal regeneration after peripheral nerve trauma; 2) attenuating excitotoxicity, apoptosis, and neuroinflammation following cerebral ischemia by regulating mitochondrial permeability, fission/fusion balance, and NLRP3 inflammasome activation; and 3) protecting retinal ganglion cells against diabetic retinopathy and glaucomatous damage via modulating oxidative stress and apoptotic signaling. Furthermore, we discuss the translational potential of PACAP, including its biomarker value in cerebrospinal fluid and plasma for injury prognosis, and the promise of innovative delivery routes to enhance brain bioavailability. By focusing on mitochondrial-centric mechanisms, this review underscores PACAP as a neuroprotective regulator and highlights its candidacy for developing next-generation neurotherapeutics.