Cellular Prion Protein Modulates Brain Mitochondrial Calcium Dynamics

Introduction: The cellular prion protein (PrPC), predominantly present in the plasma membrane of neurons, is involved in diverse signaling pathways. Its conformational conversion into the pathogenic isoform, PrP^Sc, leads to amyloid aggregation and loss of function, a central event in prion diseases. PrPC has been detected in the mitochondria of brain cells. However, its precise role in mitochondrial physiology remains largely unelucidated. Objective: This study aimed to investigate the functional role of PrPC in brain mitochondrial physiology. Methods: We used isolated brain mitochondria from wild-type (WT) and PrP knock-out (PrP-KO) mice. Mitochondrial calcium uptake was assessed by fluorescence of the calcium-sensitive probe Calcium Green 5N. We also evaluated the expression of the mitochondrial calcium uniporter (MCU) and mitochondrial hexokinase (mt-HK) via Western blot and determined mt-HK enzymatic activity spectrophotometrically, as well as the activity of α-ketoglutarate dehydrogenase fluorometrically. Results: Our results show an altered calcium dynamics in PrP-KO brain mitochondria, which uptakes higher calcium concentrations than WT mitochondria. Our data suggest a concomitant increase in the activity of the mitochondrial matrix enzyme α-ketoglutarate dehydrogenase, a calcium-cofactor-dependent enzyme. We also suggest that the enhanced calcium uptake in PrP-KO mitochondria might stem from a dysregulation of the functional interaction between PrPC and mitochondrial NMDA receptors (mNMDAR). Conclusion: Our findings suggest that PrPC is a physiological regulator of mitochondrial calcium dynamics in the brain, possibly through interaction with mNMDARs. Further investigations are crucial for a more comprehensive understanding of this intricate relationship and its implications for neuronal health and disease.