Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome.
Adolescent
Adult
Biomarkers
/ blood
Calcium
/ metabolism
Child
Endoplasmic Reticulum
/ metabolism
Energy Metabolism
Female
Fibroblasts
/ metabolism
Humans
Lactic Acid
Loss of Function Mutation
Magnetic Resonance Imaging
Male
Membrane Proteins
/ genetics
Middle Aged
Mitochondria
/ metabolism
Mutation, Missense
Tomography, Optical Coherence
Wolfram Syndrome
/ diagnosis
Young Adult
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 03 2020
16 03 2020
Historique:
received:
29
08
2019
accepted:
18
02
2020
entrez:
18
3
2020
pubmed:
18
3
2020
medline:
15
12
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32179840
doi: 10.1038/s41598-020-61735-3
pii: 10.1038/s41598-020-61735-3
pmc: PMC7075867
doi:
Substances chimiques
Biomarkers
0
Membrane Proteins
0
wolframin protein
0
Lactic Acid
33X04XA5AT
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4785Commentaires et corrections
Type : ErratumIn
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