Abstract
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 (PS1M146L). 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 PS1M146L 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.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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Funding
This study received funding from the Agencia Nacional de Promoción Científica y Tecnológica (PIBT/09-2013 to L.M. and A.C.; PICT-2015-0285 and PICT-2016-4647 to L.M.; PICT-2015-0285 and PICT-2016-4647 to C.W.), from Alzheimer Argentina to L.I.B. and from Fundacion Ciencias Biomedicas Cordoba (FUCIBICO) to A.C.
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Author contributions statement: C.W, L.M.; Methodology: C.W., P.G., M.M.R., L.G, L.C., G.V.N. N.O; E.M; A.H.R. Statistical Analysis: C.W., P.G., M.M.R., E.M.; Resources: C.W, L.I.B, E.M.C., A.C, L.M.; Writing - original draft: C.W., P.G., M.M.R., G.V.N., L.M; Writing - review & editing: C.W., P.G., M.M.R., G.V.N., L.C, L.G, N.O., E.M., A.H.R., L.I.B., E.M.C. S.C., L.M.; Supervision: A.C., L.M.; Project administration: C.W., A.C., L.M.; Funding acquisition: C.W, L.I.B., A.C, L.M. All authors read and approved the final manuscript.
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Wilson, C., Galeano, P., Remedi, M.M. et al. Mitochondrial dysfunction and Ca2+ dysregulation in human iPSC-derived neurons carrying presenilin-1 mutation arise under stress via an MCU-1-independent mechanism. Sci Rep (2026). https://doi.org/10.1038/s41598-026-35597-0
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DOI: https://doi.org/10.1038/s41598-026-35597-0
