Metabolic alterations in fibroblasts of patients presenting with the MPAN subtype of neurodegeneration with brain iron accumulation (NBIA)
Agata Wydrych, Barbara Pakuła, Patrycja Jakubek-Olszewska, Justyna Janikiewicz, Aneta M. Dobosz, Agnieszka Cudna, Marcel Rydzewski, Karolina Pierzynowska, Lidia Gaffke, Zuzanna Cyske, Estera Rintz, Iwona Kurkowska‐Jastrzębska, M. Cwyl, Paolo Pinton, Grzegorz Węgrzyn, Werner J.H. Koopman, Agnieszka Dobrzyń, Marta Skowrońska, Magdalena Lebiedzińska, Mariusz R. Wiȩckowski
Abstract
Mutations in the following genes: PANK2 , PLA2G6 , C19orf12 , WDR45 , CP , FA2H , ATP13A2 , FTL , DCAF17 , and CoASY are associated with the development of different subtypes of inherited rare disease Neurodegeneration with Brain Iron Accumulation (NBIA). Additionally, recently described mutations in FTH1 , AP4M1 , REPS1 , SCP2 , CRAT and GTPBP2 affecting iron and lipid metabolism also are thought to be involved in NBIA development. Four main subtypes, pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and beta-propeller protein-associated neurodegeneration (BPAN), are responsible for up to 82 % of all NBIA cases. Here we studied fibroblasts from 11 patients with pathogenic mutations in C19orf12 , and demonstrate various cellular aberrations. Differences between fibroblasts from healthy individuals and MPAN patients were potentiated when cells were grown under oxidative phosphorylation (OXPHOS) promoting condition suggesting an impaired metabolic flexibility. The extent of some of the cellular aberrations quantitatively correlated with disease severity, suggesting their involvement in the NBIA pathomechanism. • MPAN patients-derived fibroblasts exhibit alterations in several cellular parameters • Cellular metabolism, redox homeostasis, lipidomic profile and autophagy are altered in MPAN patients-derived fibroblasts • These differences are potentiated in the OXPHOS-promoting condition