GLP-1 and the brain's powerhouse: a new perspective on the role of mitochondria in neuroprotection.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are emerging as potential neuroprotective drugs in neurodegenerative diseases. These drugs were initially developed to manage type 2 diabetes (T2D) and obesity. In addition to GLP-1RAs having an impact on metabolic pathways, growing evidences suggests that GLP-1RAs also positively regulate mitochondrial homeostasis in several neuronal cell types such as hippocampal, cortical, dopaminergic and hypothalamic. These modulatory effect of activated GLP-1R in the brain might be playing a crucial role which ultimately leads to neuronal cell survival, synaptic function, and improve in neuroinflammation in case neurodegenerative diseases. Although GLP-1RAs show promise in enhancing mitochondrial health, major gaps remain in understanding cell-type-specific responses, sex- and age-related differences, and the precise mechanistic links between GLP-1 signaling in mitochondrial biogenesis, dynamics, and mitophagy. This review summarises current understanding of GLP-1RA-induced mitochondrial regulation in the central nervous system. It also highlights key knowledge gaps, including cell type specificity and the lack of mechanistic as well as translational studies linking GLP-1RA signalling to mitochondrial regulation in the human CNS, which must be addressed to harness their full neuroprotective potential.