Isomorphic mutation of SBDS gene is the cause of Shwachman-Diamond syndrome (SDS). SDS is a rare genetic bone marrow failure and cancer predisposition syndrome. SDS cells have altered ribosome biogenesis and protein synthesis, two high-energy consuming cellular processes. The reported increment in reactive oxygen species production, endoplasmic reticulum stress response and reduced mitochondrial functionality suggest a defect in the energy production in SDS cells.

In this study, we analyzed the energetic metabolism in SDS cells and find that the oxygen consumption is impaired when it is induced by pyruvate/malate or succinate. This induces poor ATP production and AMP accumulation with a consequent alteration in the ATP/AMP ratio. Also respiratory chain activity was impaired because of faulty function of the complex IV; this defect is not dependent from impaired protein synthesis despite ribosome biogenesis and transduction defects in SDS. In fact, COX5A and Cox2, two subunits of Complex IV encoded respectively by a nuclear and mitochondrial gene, were expressed at normal levels. Impaired function of complex IV could be due to an increment of cytoplasmic calcium concentration that inhibits complex IV activity.

Energetic stress induces changes in cellular metabolism, stimulating or inhibiting a network of molecules involved in regulation of energetic balance, such as AMPK and mTOR. In SDS cells as consequence of energetic stress, AMPK is hyper activated and the glycolytic pathway stimulated. Surprisingly, we found that also the AKT/mTOR pathway is aberrantly hyper activated since both these proteins are hyper-phosphorylated. We can speculate that hyper activation of mTOR is a way through which SDS cells support the energy defect and protein synthesis. All these defects were recovered when the SDS cells were complemented with SDS gene.

Finally, leucine is an essential amino acid that induces cell proliferation and protein synthesis, restored OXPHOS and ATP synthesis, reduced the cytoplasmic calcium concentration and the AMPK and AKT/mTOR activity, and improved in vitro erythropoiesis from SDS individuals pointing to leucine as potential tool helpful to sustain deranged energetic metabolism and erythropoiesis in SDS patients.

In conclusion, we report for the first time that SDS cells suffer of energetic stress and severe respiratory defect that is related to faulty SBSD protein. These defects are compensated by an enhanced activation of AMPK, glycolysis and mTOR/Akt pathways, which appear to adequately support protein synthesis. A pivotal role in the maintenance of this altered metabolism could be played by altered calcium homeostasis. Noteworthy biochemical defects might be largely corrected by leucine which also favourably affects in vitro erythropoiesis thus pointing to biochemical defects as important determinant for impaired hematopoiesis od SDS.


Dufour:Pfizer: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.