Dysregulation of energy metabolism and calcium homeostasis in iPSC-derived neurons carrying Presenilin-1 M146L gene mutation

Impaired cellular activities, particularly in highly active cells such as neurons, are primarily supported by metabolic abnormalities and failures in Ca²⁺ homeostasis. Here, we provide an integrative analysis of human iPSC-derived neurons (iNs) carrying the Presenilin-1 M146L gene mutation (PS1 ^M146L ) and control cells (PS1 ^control ). PS1 ^M146L iNs exhibited abnormal Ca²⁺ dynamics, a significant increase in key parameters of mitochondrial respiration, and higher intracellular ROS levels. KCl-evoked depolarisation was significantly lower in PS1 ^M146L , suggesting a failure in maintaining the electrochemical gradient across the plasma membrane. Following thapsigargin stimulation, mitochondrial Ca²⁺ levels ([Ca²⁺]m) were significantly reduced in PS1 ^M146L, while [Ca²⁺]m did not differ significantly between genotypes after treatment with bradykinin, suggesting that impairments in the [Ca²⁺]m homeostasis are particularly evident under stress conditions and do not impact the 1,4,5-triphosphate (IP3) pathway. Since iNs of both genotypes were sensitive to the MCU-1 inhibitor, the deficits observed in PS1 ^M146L could be the consequence of impairments in the ER-mitochondria contacts. Our results illustrate the utility of iNs carrying PS1 mutations in understanding how human neurons alter relevant pathways before neurodegeneration.