Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Abstract

Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.

Keywords: cancer; electron transport chain (ETC); metabolism; metabolites; microbiota; mitochondria; mitochondria exchange; mitochondrial DNA (mtDNA); therapy; tricarboxylic acid (TCA) cycle.

Figure 1

Oxidative phosphorylation (OXPHOS) through the electron transport chain (ETC) and adenosine triphosphate (ATP) production. OXPHOS is the process leading to ATP synthesis through the transport of electrons released by the oxidation of nicotinamide adenine dinucleotide (NADH) and succinate generated by the tricarboxylic acid (TCA) cycle. The transport of electrons is mediated by the ETC located in the mitochondrial inner membrane. The ETC is composed of the four complexes NADH–ubiquinone oxidoreductase (complex I), succinate–CoQ oxidoreductase (complex II), ubiquinol–cytochrome c oxidoreductase (complex III), and cytochrome c oxidase (complex IV), and of the free-electron carriers ubiquinone (CoQ10) and cytochrome c (CytC). Electrons are transferred through the ETC and finally to oxygen (O₂) (dashed lines). This electron transfer is accompanied by a flow of protons (H⁺) from the mitochondrial matrix into the intermembrane space, across complexes I, III, and IV. The generated transmembrane electrochemical proton gradient allows the ATP synthase (complex V) to produce ATP. Also shown is the dihydroorotate dehydrogenase (DHODH), which participates in the electron transfer process through the oxidation of dihydroorotate to orotate, leading to de novo pyrimidine synthesis.

Figure 2

Effects of complex I mutations. (1) As a result of complete loss of complex I, NADH inhibits the TCA cycle enzyme α-ketoglutarate dehydrogenase (αKGDH). This increases α-ketoglutarate levels and results in HIF1α inhibition. (2–4) Complex I mutations increase reactive oxygen species (ROS) production. (2) ROS activate pyruvate dehydrogenase kinase (PDK2), which inhibits pyruvate dehydrogenase (PDH). Pyruvate accumulation activates HIF1α. (3) ROS activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/hypoxia-inducible factor 1 alpha (HIF1α) signaling pathway. (4) Mitochondrial ROS activate the NADPH oxidase, which produces cytoplasmic superoxide. ROS lead to genomic instability via double-strand breaks (DSBs) and activate the cellular anti-oxidant responses.

Figure 3

Role of TCA cycle intermediates in HIF1α stabilization and nuclear epigenetic modifications. Following its hydroxylation by prolyl-hydroxylases (PHDs), HIF1α is recognized by the von Hippel–Lindau (VHL) complex that targets it for proteasomal degradation. The inactivation of complex II of the ETC leads to ROS accumulation and inhibition of PHD activity by succinate, preventing HIF1α hydroxylation and degradation. Upon translocation to the nucleus, HIF1α binds to the hypoxic response element (HRE) and activates gene transcription, contributing to tumorigenesis. Complex II-deficient cells primarily rely on glutamine to fuel the TCA cycle and utilize oxaloacetate to generate aspartate for their biosynthetic pathways. The TCA cycle also produces metabolites that act as epigenetic modifiers. The α-ketoglutarate is a cofactor of 2-oxoglutarate-dependent dioxygenases, including the ten-eleven translocation (TET) family of DNA demethylases and the histone lysine demethylase (KDM) family. The metabolites 2-hydroxyglutarate, succinate, and fumarate, which are structurally similar to α-ketoglutarate, act as antagonists of TET- and KDM-catalyzed reactions.

Figure 4

The mevalonate and the fatty acid synthesis pathways. Acetyl-CoA, derived from glucose, glutamine, or citrate following its export to the cytosol, is converted through the mevalonate pathway into several metabolites including cholesterol and coenzyme Q10. Coenzyme Q10 transfers electrons from complexes I and II of the electron transport chain, as well as from dihydroorotate dehydrogenase (DHODH), to complex III. Acetyl-coA also acts a precursor for fatty acid synthesis, through its conversion to malonyl-CoA, and then to palmitate. The mevalonate pathway is represented in yellow boxes. The fatty acid synthesis pathway is represented in blue boxes. Dashed arrows represent multiple steps. HMG-CoA, 3-hydroxy-3-methylglutaryl CoA; IPP, isopentenyl-diphosphate; FPP, farnesyl diphosphate; GGPP, geranylgeranyl-diphosphate; TCA cycle, tricarboxylic acid cycle.