Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Abstract

Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia-induced changes in the proteome mediated by the activity of transcription factors such as hypoxia-inducible factor 1. Hypoxia is a well-described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer-associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272-285. doi: 10.1002/wsbm.1334 For further resources related to this article, please visit the WIREs website.

Figure 1

Hypoxia‐induced changes in mitochondrial metabolism. Changes that have been described to occur in human mitochondria under hypoxia are shown on a background of normoxic metabolism. Hypoxia‐induced changes in pathway use are shown as thicker lines, while the reversal of succinate dehydrogenase (SDH) activity is shown as a blue line. Metabolic enzymes are shown in red. Abbreviations: AcCoA, acetyl CoA; ACO1, cytosolic aconitase; ACO2, mitochondrial aconitase; ADSS, adenylosuccinate synthetase; ADSL, adenylosuccinate lyase; a‐KG, α‐ketoglutarate; a‐KGDH, α‐ketoglutarate dehydrogenase; Asp, aspartate; Cit, citrate; FAD⁺, flavin adenine dinucleotide; FADH₂, reduced flavin adenine dinucleotide; Fum, fumarate; Glc, glucose; Gln, glutamine; Glu, glutamate; IDH1, cytosolic isocitrate dehydrogenase; IDH2, mitochondrial isocitrate dehydrogenase; Lac, lactate; LDH, lactate dehydrogenase; Mal, malate; NAD⁺, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; OAA, oxaloacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; Pyr, pyruvate; ROS, reactive oxygen species; Suc, succinate.

Figure 2

Succinate dehydrogenase (SDH) (a) and fumarate hydratase (FH) (b) mutation‐mediated alterations in mitochondrial metabolism. Metabolic pathways that have been shown to be used in cells or tumors containing these mutations are shown. Pathways that are likely to be used, but have not yet been shown are marked with ‘?’ Abbreviations: AcCoA, acetyl CoA; ACO2, mitochondrial aconitase; a‐KG, α‐ketoglutarate; Asp, aspartate; BR, bilirubin; BV, biliverdin; Cit, citrate; Fum, fumarate; Glc, glucose; Gln, glutamine; Glu, glutamate; GSH, reduced glutathione; Gly, glycine; Lac, lactate; OAA, oxaloacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; Pyr, pyruvate; Suc, succinate.