Mitochondrial alterations are linked to various brain diseases, including Alzheimer’s disease and psychiatric disorders. However, whether they are a cause or consequence of a given disease remains elusive owing to a lack of tools that allow the precise modification of mitochondrial metabolism. In a paper in Nature Neuroscience, Pagano Zottola et al. generated mutant G protein-coupled receptors (GPCRs) to modulate mitochondrial G protein signaling. Their work uncovers a potential causal link between mitochondrial dysfunction and dementia, which might be further explored as a therapeutic pathway to improve cognition.
Previous observations showed that G proteins in mitochondria can modulate oxidative phosphorylation and mitochondrial dynamics. The authors generated mutant GPCRs using designer receptors exclusively activated by designer drug (DREADD) technology to manipulate the G protein Gs. In vitro activation of the DREADDs, called mitoDREADD-Gs, triggered a signaling pathway involving Gs and protein kinase A, which boosted mitochondrial activity.
