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

Abstract

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.

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“…In particular, it appears that a defect of the respiratory chain in FA cells increases oxidative stress and that this is associated with glucose dysmetabolism and insulin resistance, chromosome instability, reduced metalloproteases activity and cytotoxic effects of tumour necrosis factor-alpha. Recently it has been shown that FA cells try to compensate for the mitochondria impairment by enhancing the glycolysis pathway, although this metabolic shift does not completely restore the energetic status (Cappelli et al, 2017). Lipid metabolism, which is mainly composed of beta-oxidation and lipid synthesis according to the energetic need of the cell, is another pathway involved in cellular energy balance.…”

“…We have previously demonstrated that FA cells preferentially convert glucose to lactate rather than use it for the aerobic metabolism, despite the normal activity of pyruvate dehydrogenase (Cappelli et al, 2017). However, when analysing the intracellular concentration of Acetyl CoA (AcCoA), we have observed that FA cells displayed a higher concentration with In particular, the panel reports the Acetyl-CoA concentration and the activities of 3-hydroxyacyl-CoA dehydrogenase, as markers of beta-oxidation, and b-ketoacyl-ACP reductase and Enoyl-ACP-reductase assay, as markers of fatty acid synthesis, and the lipid content.…”

Altered lipid metabolism could drive the bone marrow failure in fanconi anaemia

“…In particular, it appears that a defect of the respiratory chain in FA cells increases oxidative stress and that this is associated with glucose dysmetabolism and insulin resistance, chromosome instability, reduced metalloproteases activity and cytotoxic effects of tumour necrosis factor‐alpha. Recently it has been shown that FA cells try to compensate for the mitochondria impairment by enhancing the glycolysis pathway, although this metabolic shift does not completely restore the energetic status (Cappelli et al , ).…”

“…We have previously demonstrated that FA cells preferentially convert glucose to lactate rather than use it for the aerobic metabolism, despite the normal activity of pyruvate dehydrogenase (Cappelli et al , ). However, when analysing the intracellular concentration of Acetyl CoA (AcCoA), we have observed that FA cells displayed a higher concentration with respect to the control and corrected samples (Fig A).…”

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures

“…Even though both siblings described here did not have hematological features and chromosome breakage studies consistent with Fanconi anemia, other hematological disorders such as sideroblastic anemia have been well described in multisystemic mitochondrial disorders such as Pearson syndrome, MLASA syndrome (mitochondrial myopathy, lactic acidosis, and SA) and complex I deficiency associated with a hemizygous change in NDUFB11 (Falcon & Howard, ; Lichtenstein et al, ; Riley et al, ; Tesarova et al, ). However, it was not until recently that defective oxidative metabolism and mitochondrial localization along with spontaneous mitochondrial fragmentation have been described in Fanconi anemia cells (Bottega et al, ; Cappelli et al, ; Pagano, Shyamsunder, Verma, & Lyakhovich, ). Imbalance of NAD + /NADH in COX deficiency has been postulated as the underlying mechanism of DNA instability and increased double‐stranded DNA breaks (Douiev & Saada, ).…”