Mitochondrial dysfunction and Ca(2+) dysregulation in human iPSC-derived neurons carrying presenilin-1 mutation arise under stress via an MCU-1-independent mechanism.

Impaired cellular activities in Alzheimer’s disease (AD) are linked to metabolic defects and Ca²⁺ dysregulation, but the underlying mechanisms in human neurons are unclear. We performed an integrative analysis using human iPSC-derived neurons (iNs) carrying the Presenilin-1 M146L mutation (PS1(M146L)). Mutant iNs displayed abnormal Ca²(+) dynamics, enhanced mitochondrial respiration, and elevated reactive oxygen species (ROS). KCl-evoked depolarization was reduced, indicating a compromised plasma membrane electrochemical gradient. Under thapsigargin-induced stress, mitochondrial Ca²⁺ ([Ca²⁺]m) was significantly lower in PS1(M146L) iNs, while bradykinin stimulation (implying an intact IP3 pathway) showed no genotypic difference. Since both genotypes remained sensitive to an MCU-1 inhibitor, the observed [Ca²⁺]m deficits likely stem from impaired ER-mitochondria contacts rather than MCU-1 dysfunction. The present results generalise previous observations and provide evidence of the role of the MCU-1 on Ca²⁺ homeostasis in human neurons bearing this specific familial AD mutation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-35597-0.