Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome.
Chiara La MorgiaAlessandra MarescaGiulia AmoreLaura Ludovica GramegnaMichele CarbonelliEmanuela ScimonelliAlberto DaneseSimone PatergnaniLeonardo CaporaliFrancesca TagliaviniValentina Del DottoMariantonietta CapristoFederico SadunPiero BarboniGiacomo SaviniStefania EvangelistiClaudio BianchiniMaria Lucia ValentinoRocco LiguoriCaterina TononCarlotta GiorgiPaolo PintonRaffaele LodiValerio CarelliPublished in: Scientific reports (2020)
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.
Keyphrases
- endoplasmic reticulum
- optical coherence tomography
- magnetic resonance imaging
- end stage renal disease
- oxidative stress
- newly diagnosed
- ejection fraction
- diabetic retinopathy
- lactic acid
- cell death
- skeletal muscle
- risk assessment
- white matter
- prognostic factors
- peritoneal dialysis
- extracellular matrix
- physical activity
- autism spectrum disorder
- high intensity
- cell therapy
- multiple sclerosis
- small molecule
- high resolution
- resting state
- quantum dots
- single cell
- resistance training
- mass spectrometry
- duchenne muscular dystrophy
- amino acid
- atomic force microscopy
- body composition
- breast cancer cells
- weight loss
- living cells
- network analysis
- peripheral nerve