Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome: Scientific Reports

C. La Morgia, A. Maresca, G. Amore, L.L. Gramegna, M. Carbonelli, E. Scimonelli, A. Danese, S. Patergnani, L. Caporali, F. Tagliavini, V. Del Dotto, M. Capristo, F. Sadun, P. Barboni, G. Savini, S. Evangelisti, C. Bianchini, M.L. Valentino, R. Liguori, C. TononC. Giorgi, P. Pinton, R. Lodi, V. Carelli

Research output: Contribution to journalArticlepeer-review

Abstract

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria. © 2020, The Author(s).
Original languageEnglish
JournalSci. Rep.
Volume10
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • biological marker
  • calcium
  • lactic acid
  • membrane protein
  • wolframin protein
  • adolescent
  • adult
  • blood
  • child
  • endoplasmic reticulum
  • energy metabolism
  • female
  • fibroblast
  • genetics
  • human
  • loss of function mutation
  • male
  • metabolism
  • middle aged
  • missense mutation
  • mitochondrion
  • nuclear magnetic resonance imaging
  • optical coherence tomography
  • pathology
  • ultrastructure
  • Wolfram syndrome
  • young adult
  • Adolescent
  • Adult
  • Biomarkers
  • Calcium
  • Child
  • Endoplasmic Reticulum
  • Energy Metabolism
  • Female
  • Fibroblasts
  • Humans
  • Lactic Acid
  • Loss of Function Mutation
  • Magnetic Resonance Imaging
  • Male
  • Membrane Proteins
  • Middle Aged
  • Mitochondria
  • Mutation, Missense
  • Tomography, Optical Coherence
  • Wolfram Syndrome
  • Young Adult

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