TCA Cycle Defects and Cancer: When Metabolism Tunes Redox State

Simone Cardaci,Maria Rosa Ciriolo

doi:10.1155/2012/161837

Simone Cardaci, Maria Rosa Ciriolo

Open Access

https://doi.org/10.1155/2012/161837

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Abstract

Inborn defects of the tricarboxylic acid (TCA) cycle enzymes have been known for more than twenty years. Until recently, only recessive mutations were described which, although resulted in severe multisystem syndromes, did not predispose to cancer onset. In the last ten years, a causal role in carcinogenesis has been documented for inherited and acquired alterations in three TCA cycle enzymes, succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH), pointing towards metabolic alterations as the underlying hallmark of cancer. This paper summarizes the neoplastic alterations of the TCA cycle enzymes focusing on the generation of pseudohypoxic phenotype and the alteration of epigenetic homeostasis as the main tumor-promoting effects of the TCA cycle affecting defects. Moreover, we debate on the ability of these mutations to affect cellular redox state and to promote carcinogenesis by impacting on redox biology.

Highlights

Cancer cells differ from normal ones due to a plethora of oncogenes-driven biochemical changes designed to sustain an high rate of growth and proliferation [1]
Emerging findings from the last year support the hypothesis that, in several cell systems such as (i) cancer cells containing mutations in complex I or complex III of the electron transport chain (ETC), (ii) patient-derived renal carcinoma cells with mutations in fumarate hydratase (FH), (iii) cells with normal mitochondria subjected to acute pharmacological ETC, inhibition, as well as (iv) tumor cells exposed to hypoxia, the first stage of the cycle can proceed in the opposite direction through the reductive carboxylation of α-KG to form citrate
Whereas IDH1 is found into cytoplasm and peroxisomes, IDH2 and IDH3 are exclusively localized into the mitochondrial matrix, and, all three isoforms are able to decarboxylate isocitrate, IDH3 is the main form of isocitrate dehydrogenase (IDH) functioning in the tricarboxylic acid (TCA) cycle under physiological conditions whereas IDH1 and IDH2 are mainly involved in the reductive glutamine metabolism, under hypoxia and ETC alterations [4, 5, 23]

Summary

Introduction

Cancer cells differ from normal ones due to a plethora of oncogenes-driven biochemical changes designed to sustain an high rate of growth and proliferation [1]. In the last decade, the discovery that inherited and acquired alterations in some enzymes of tricarboxylic acid (TCA) cycle have a causal role in carcinogenesis has changed this viewpoint, pointing towards altered metabolism as the underlying hallmark of neoplastic transformation. These alterations consist of germline defects in genes encoding subunits of SDH and FH, as well as somatic mutations in coding sequence for IDH. In this paper, we summarize the prooncogenic defects in the TCA cycle enzymes discussing their involvement in the tuning of redox environment and the engagement of redoxdependent tumorigenic signaling

Fundamentals of the TCA Cycle

Genetic Defects in the TCA Cycle

Mechanisms of Tumorigenesis Caused by the TCA Cycle Defects

Redox-Dependent Tumorigenic Alterations Elicited by the TCA Cycle Defects

Findings

Concluding Remarks