Pheochromocytomas and Paragangliomas: Bypassing Cellular Respiration

Abstract

Abstract: Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that show the highest heritability of all human neoplasms and represent a paradoxical example of genetic heterogeneity. Amongst the elevated number of genes involved in the hereditary predisposition to the disease (at least nineteen) there are eleven tricarboxylic acid (TCA) cycle-related genes, some of which are also involved in the development of congenital recessive neurological disorders and other cancers such as cutaneous and uterine leiomyomas, gastrointestinal tumors and renal cancer. Somatic or germline mutation of genes encoding enzymes catalyzing pivotal steps of the TCA cycle not only disrupts cellular respiration, but also causes severe alterations in mitochondrial metabolite pools. These latter alterations lead to aberrant accumulation of "oncometabolites" that, in the end, may lead to deregulation of the metabolic adaptation of cells to hypoxia, inhibition of the DNA repair processes and overall pathological changes in gene expression. In this review, we will address the TCA cycle mutations leading to the development of PPGL, and we will discuss the relevance of these mutations for the transformation of neural crest-derived cells and potential therapeutic approaches based on the emerging knowledge of underlying molecular alterations.

Keywords: TCA cycle; germline mutation; paraganglioma; pheochromocytoma.

Figure 1

Schematic representation of the enzymes and mitochondrial metabolic pathways, tricarboxylic acid (TCA) cycle, malate/aspartate shuttle, nicotinamide adenine dinucleotide (NADH) exchange and metabolite efflux from the mitochondria, involved in pheochromocytoma and paraganglioma (PPGL) development and/or neurodegenerative disorders. Enzymes reported as altered in PPGL are denoted in red capital letters. Enzymes involved in neurodegenerative disorders are denoted with an asterisk. SLC25A11: solute carrier family 25 member 11; SLC25A12/SLC25A13: carriers solute carrier family 25 members 12/13; SLC25A1: solute carrier family 25 member 1; SLC25A19: solute carrier family 25 member 19; GOT2: mitochondrial glutamic-oxaloacetic transaminase 2; FH: fumarate hydratase; MDH2: mitochondrial malate dehydrogenase; CS: citrate synthase; ACO2: mitochondrial aconitase; IDH2: isocitrate dehydrogenase 2; IDH3A/IDH3B/IDH3G: subunits of isocitrate dehydrogenase 3; L2HGDH: L-2-hydroxyglutarate dehydrogenase; OGDH/DLD/DLST: subunits of the αKG (alpha-ketoglutarate) dehydrogenase complex; SUCLA2/SUCLG1/SUCLG2: subunits of succinyl-CoA synthetase; SDHA/B/C/D: subunits of the succinate dehydrogenase complex; SDHAF1/SDHAF2: succinate dehydrogenase assembly factors; αKG: α-ketoglutarate; TPP: thiamine pyrophosphate.

Figure 2

Schematic representation of the consequences of tricarboxylic acid (TCA) cycle disruption in pheochromocytomas and paragangliomas (PPGL). Upon disruption of the activity of pivotal TCA cycle enzymes, there is an accumulation of metabolites (i.e., succinate, fumarate, D2HG and L2HG). Their efflux from the mitochondria to the cytosol and their subsequent competition with α-ketoglutarate lead to the inhibition of α-ketoglutarate-dependent dioxygenases involved in DNA and histone demethylation, regulation of HIF, and homologous recombination. As a result, different mechanisms are proposed as the cause of tumorigenesis in PPGL: aberrant global hypermethylation (CIMP), activation of the HIF pathway and decreased DNA repair. Finally, different therapeutic options may target each altered pathway: demethylating agents, HIF inhibitors, and poly-(ADP-ribose)-polymerase (PARP) inhibitors, respectively. D2HG: D-2-hydroxyglutarate; L2HG: L-2-hydroxyglutarate; TET: ten-eleven translocation DNA hydroxylase; JMJ: Jumonji; KDM: histone lysine demethylase; PHDs: prolyl hydroxylase domain-containing proteins; HIF: hypoxia-inducible factor; CIMP: CpG island methylation phenotype.