Patient iPSC ‐derived astrocytes reveal impaired homeostasis and reactive‐like features in propionic acidemia

Abstract Propionic acidemia (PA) is a neurometabolic disorder caused by propionyl‐CoA carboxylase deficiency with frequent neurological involvement, yet cell‐type‐specific mechanisms remain poorly defined. We established human induced pluripotent stem cell (iPSC)‐derived astrocytes (iAs) from patients harboring PCCA or PCCB mutations and investigated functional and molecular alterations associated with PA. Both control‐ and patient‐derived iPSCs yielded astrocyte‐enriched cultures through a neural progenitor intermediate, with expression of astrocyte‐associated markers. Patient iAs showed impaired mitochondrial respiration (lower basal and maximal oxygen consumption and ATP‐linked respiration), together with reduced high‐affinity uptake of glutamate and glycine neurotransmitters and evidence of disturbed Ca 2+ homeostasis. They also migrated faster in wound‐healing assays and displayed reactive‐like features, including increased GFAP and connexin 43 (Cx43) protein levels and elevated AQP4 mRNA levels. Targeted miRNA profiling revealed upregulation of miR‐124‐3p, miR‐9‐5p, and miR‐125b‐5p, concomitant with downregulation of miR‐146a‐5p, miR‐155‐5p, and miR‐145‐5p. Consistent with these changes, reported target genes associated with innate immune signaling ( IRAK1 , TRAF6 , TAB2 ), astrocyte remodeling ( GFAP ), and water/ion homeostasis ( AQP4 ) were upregulated. Inflammatory and proliferative markers were likewise increased, including IL1B , TNF , and MKI67 . Together, these convergent alterations suggest a phenotype characterized by impaired homeostatic functions and reactive‐like features, which may heighten neural network vulnerability under metabolic stress. Collectively, our data support astrocyte dysfunction as a potential contributor to PA neuropathology and highlight patient‐derived iAs as a useful model for future mechanistic studies and therapeutic exploration. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.