A Multidrug Approach to Modulate the Mitochondrial Metabolism Impairment and Relative Oxidative Stress in Fanconi Anemia Complementation Group A.

Enrico Cappelli,Stefano Regis,Fabio Corsolini,Paolo Degan,Barbara Banelli,Nadia Bertola,Carlo Dufour,Silvia Ravera,Silvia Bruno

doi:10.3390/metabo12010006

Abstract

Fanconi Anemia (FA) is a rare recessive genetic disorder characterized by aplastic anemia due to a defective DNA repair system. In addition, dysfunctional energy metabolism, lipid droplets accumulation, and unbalanced oxidative stress are involved in FA pathogenesis. Thus, to modulate the altered metabolism, Fanc-A lymphoblast cell lines were treated with quercetin, a flavonoid compound, C75 (4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid), a fatty acid synthesis inhibitor, and rapamycin, an mTOR inhibitor, alone or in combination. As a control, isogenic FA cell lines corrected with the functional Fanc-A gene were used. Results showed that: (i) quercetin recovered the energy metabolism efficiency, reducing oxidative stress; (ii) C75 caused the lipid accumulation decrement and a slight oxidative stress reduction, without improving the energy metabolism; (iii) rapamycin reduced the aerobic metabolism and the oxidative stress, without increasing the energy status. In addition, all molecules reduce the accumulation of DNA double-strand breaks. Two-by-two combinations of the three drugs showed an additive effect compared with the action of the single molecule. Specifically, the quercetin/C75 combination appeared the most efficient in the mitochondrial and lipid metabolism improvement and in oxidative stress production reduction, while the quercetin/rapamycin combination seemed the most efficient in the DNA breaks decrement. Thus, data reported herein suggest that FA is a complex and multifactorial disease, and a multidrug strategy is necessary to correct the metabolic alterations.

Highlights

Fanconi Anemia (FA) is a rare autosomal or X-linked recessive disease [1], characterized by bone marrow failure and aplastic anemia, which represent the primary causes of death [2]
The experiments reported in this manuscript were done in the presence of the following molecules: (i) quercetin, an antioxidant molecule, (ii) C75, (4-Methylene-2-octyl5-oxotetrahydrofuran-3-carboxylic acid) an inhibitor of fatty acid synthesis, and (iii) rapamycin, a modulator of pathways involved in mitochondrial metabolism
The link between pathogenic variants of FA genes and altered energy metabolism was not yet described, these biochemical alterations appear to play a pivotal role in the disease, suggesting that FA should be considered a multifactorial disease

Summary

Introduction

Fanconi Anemia (FA) is a rare autosomal or X-linked recessive disease [1], characterized by bone marrow failure and aplastic anemia, which represent the primary causes of death [2]. 23 genes are involved in FA [3], which codify for proteins involved in a complex enlisted in response to genotoxic insults [4,5] Their pathogenic variants induce a defect in the DNA repair mechanisms and the cell cycle arrest in the G2 phase [6]. The metabolic impairments in FA cells are correlated with insulin resistance (IR) and other clinical effects as obesity, and dyslipidemia, frequently observed in FA patients [24,25]. All these metabolic alterations are visible only in normoxic conditions, while in the bone marrow niche, a hypoxic environment, the mitochondrial defect is not detectable [26]

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