Defects in mitochondrial energetic function compels Fanconi Anaemia cells to glycolytic metabolism

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1863

Article

Cappelli, Enrico¹  Cuccarolo, Paola^2,6  Stroppiana, Giorgia³  Miano, Maurizio¹  Bottega, Roberta⁴  Cossu, Vanessa⁵  Degan, Paolo²  Ravera, Silvia⁵ 

[1] Ist Giannina Gaslini, Hematol Unit, I-16148 Genoa, Italy

[2] IRCCS AOU San Martino, UO Mutagenesis, IST Ist Nazl Ric Canc, Largo Rosanna Benzi 10, I-16132 Genoa, Italy

[3] Ist Giannina Gaslini, Lab Diag Pre & Postnatale Malattie Metab, I-16148 Genoa, Italy

[4] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy

[5] Univ Genoa, Dipartimento Farm, Lab Biochim, Genoa, Italy

[6] IRCCS Mario Negri, V GB Camozzi 3, I-24020 Bergamo, Italy

关键词: Fanconi Anaemia;    Energy metabolism;    Glycolysis;    Oxidative phosphorylation;    Oxidative stress;    Cancer-prone diseases;   

DOI  :  10.1016/j.bbadis.2017.03.008

来源: Elsevier

【 摘 要 】

Energetic metabolism plays an essential role in the differentiation of haematopoietic stem cells (HSC). In Fanconi Anaemia (FA), DNA damage is accumulated during HSC differentiation, an event that is likely associated with bone marrow failure (BMF). One of the sources of the DNA damage is altered mitochondrial metabolism and an associated increment of oxidative stress. Recently, altered mitochondrial morphology and a deficit in the energetic activity in FA cells have been reported. Considering that mitochondria are the principal site of aerobic ATP production, we investigated FA metabolism in order to understand what pathways are able to compensate for this energy deficiency. In this work, we report that the impairment in mitochondrial oxidative phosphorylation (OXPHOS) in FA cells is countered by an increase in glycolytic flux. By contrast, glutaminolysis appears lower with respect to controls. Therefore, it is possible to conclude that in FA cells glycolysis represents the main pathway for producing energy, balancing the NADH/NAD(+) ratio by the conversion of pyruvate to lactate. Finally, we show that a forced switch from glycolytic to OXPHOS metabolism increases FA cell oxidative stress. This could be the cause of the impoverishment in bone marrow HSC during exit from the homeostatic quiescent state. This is the first work that systematically explores FA energy metabolism, highlighting its flaws, and discusses the possible relationships between these defects and BMF.

【 授权许可】

Free