Fig. 1: Metabolic adaptations in FH-deficient cells.

FH loss leads to the truncation of the TCA cycle and subsequent accumulation of fumarate (highlighted in orange). Mitochondrial respiration is significantly reduced due to the loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of the electron transport chain (ETC) and the inhibition of Succinate Dehydrogenase (Complex II of the ETC). Because of this, cells increase the glycolytic flux by taking up glucose and producing lactate to obtain energy. Furthermore, part of the carbons from glucose is diverted towards the pentose phosphate pathway (PPP) to maintain the redox homeostasis producing NADPH (purple arrows). Moreover, to maintain the remaining TCA activity FH-deficient cells increase glutamine uptake and oxidation (green arrows). On the one hand, glutamine-derived carbons are metabolized to fumarate and and bilirubin (secreted to the media) produced via the haem pathway (red arrows). On the other hand, glutamine carbons are used through reductive carboxylation to increase fatty acid (FA) synthesis (yellow arrows). Due to the accumulation of fumarate up to millimolar levels, FH-deficient cells activate multiple strategies to buffer the potential toxicity. For example, fumarate can permeate to the nucleus and also be secreted extracellularly. In the cytoplasm, fumarate accumulation leads to aberrant production of argininosuccinate via the reverse reaction of argininosuccinate lyase (ASL) in the urea cycle (grey arrows). In this context, it is important to remark that FH-deficient cells depend on a constant uptake of extracellular arginine, which becomes essential for the viability of these cells, to maintain this buffering system. Finally, fumarate can also alter PNC (Purine Nucleotide Cycle), where the increase of fumarate causes the reversal of adenylosuccinate lyase (ADSL) to form adenylosuccinate, altering de novo purine biosynthesis and making cells reliant on the salvage pathway to support purine synthesis. ATP Adenosine Triphosphate, SDH Succinate Dehydrogenase, ACO2 Aconitase2, OAA Oxaloacetate, NADH Nicotinamide adenine dinucleotide, IMP Inosine Monophosphate, AMP Adenosine Monophosphate, CI-V Electron transport chain Complex I–V), SAICAR succinyl-5-aminoimidazole-4-carboxamide-1-ribose-5′-phosphate, AICAR 5-Amino-1-(5-Phospho-D-ribosyl)imidazole-4-carboxamide.