Evaluation of energy metabolism and calcium homeostasis in cells affected by Shwachman-Diamond syndrome

Silvia Ravera, Carlo Dufour, Simone Cesaro, Roberta Bottega, Michela Faleschini, Paola Cuccarolo, Fabio Corsolini, Cesare Usai, Marta Columbaro, Marco Cipolli, Anna Savoia, Paolo Degan, Enrico Cappelli

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Abstract

Isomorphic mutation of the SBDS gene causes Shwachman-Diamond syndrome (SDS). SDS is a rare genetic bone marrow failure and cancer predisposition syndrome. SDS cells have ribosome biogenesis and their protein synthesis altered, which are two high-energy consuming cellular processes. The reported changes in reactive oxygen species production, endoplasmic reticulum stress response and reduced mitochondrial functionality suggest an energy production defect in SDS cells. In our work, we have demonstrated that SDS cells display a Complex IV activity impairment, which causes an oxidative phosphorylation metabolism defect, with a consequent decrease in ATP production. These data were confirmed by an increased glycolytic rate, which compensated for the energetic stress. Moreover, the signalling pathways involved in glycolysis activation also appeared more activated; i.e. we reported AMP-activated protein kinase hyper-phosphorylation. Notably, we also observed an increase in a mammalian target of rapamycin phosphorylation and high intracellular calcium concentration levels ([Ca2+]i), which probably represent new biochemical equilibrium modulation in SDS cells. Finally, the SDS cell response to leucine (Leu) was investigated, suggesting its possible use as a therapeutic adjuvant to be tested in clinical trials.

Original languageEnglish
Article number25441
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - May 5 2016

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Energy Metabolism
Homeostasis
Calcium
Phosphorylation
Bone Neoplasms
AMP-Activated Protein Kinases
Endoplasmic Reticulum Stress
Oxidative Phosphorylation
Glycolysis
Sirolimus
Shwachman syndrome
Ribosomes
Leucine
Reactive Oxygen Species
Adenosine Triphosphate
Bone Marrow
Clinical Trials
Mutation
Genes
Proteins

ASJC Scopus subject areas

  • General

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Evaluation of energy metabolism and calcium homeostasis in cells affected by Shwachman-Diamond syndrome. / Ravera, Silvia; Dufour, Carlo; Cesaro, Simone; Bottega, Roberta; Faleschini, Michela; Cuccarolo, Paola; Corsolini, Fabio; Usai, Cesare; Columbaro, Marta; Cipolli, Marco; Savoia, Anna; Degan, Paolo; Cappelli, Enrico.

In: Scientific Reports, Vol. 6, 25441, 05.05.2016.

Research output: Contribution to journalArticle

Ravera, S, Dufour, C, Cesaro, S, Bottega, R, Faleschini, M, Cuccarolo, P, Corsolini, F, Usai, C, Columbaro, M, Cipolli, M, Savoia, A, Degan, P & Cappelli, E 2016, 'Evaluation of energy metabolism and calcium homeostasis in cells affected by Shwachman-Diamond syndrome', Scientific Reports, vol. 6, 25441. https://doi.org/10.1038/srep25441
Ravera, Silvia ; Dufour, Carlo ; Cesaro, Simone ; Bottega, Roberta ; Faleschini, Michela ; Cuccarolo, Paola ; Corsolini, Fabio ; Usai, Cesare ; Columbaro, Marta ; Cipolli, Marco ; Savoia, Anna ; Degan, Paolo ; Cappelli, Enrico. / Evaluation of energy metabolism and calcium homeostasis in cells affected by Shwachman-Diamond syndrome. In: Scientific Reports. 2016 ; Vol. 6.
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