The bioenergetic landscape of cancer

Abstract

Background: Bioenergetic remodeling of core energy metabolism is essential to the initiation, survival, and progression of cancer cells through exergonic supply of adenosine triphosphate (ATP) and metabolic intermediates, as well as control of redox homeostasis. Mitochondria are evolutionarily conserved organelles that mediate cell survival by conferring energetic plasticity and adaptive potential. Mitochondrial ATP synthesis is coupled to the oxidation of a variety of substrates generated through diverse metabolic pathways. As such, inhibition of the mitochondrial bioenergetic system by restricting metabolite availability, direct inhibition of the respiratory Complexes, altering organelle structure, or coupling efficiency may restrict carcinogenic potential and cancer progression.

Scope of review: Here, we review the role of bioenergetics as the principal conductor of energetic functions and carcinogenesis while highlighting the therapeutic potential of targeting mitochondrial functions.

Major conclusions: Mitochondrial bioenergetics significantly contribute to cancer initiation and survival. As a result, therapies designed to limit oxidative efficiency may reduce tumor burden and enhance the efficacy of currently available antineoplastic agents.

Keywords: Bioenergetics; Cancer; Cell survival; Energy transformation; Mitochondria.

Figure 1

Structural overview of the mitochondrion. On an ultrastructural level, mitochondrion contain an outer membrane (mtOM), inner membrane (mtIM), intermembrane space (iMS) between the double membranes, and the matrix within the mtIM. The mtIM contains numerous invaginations, referred to as cristae, and is further distinguished as 1) the membrane near the mtOM (the inner boundary membrane) or 2) the membrane of the cristae (the crystal membrane). The cristae structure allows for increased surface area and a distinct microenvironment of the intracristal space, separate from the remaining peripheral space of the IMS, and the intercristal space, separate from other parts of the matrix. Despite having distinct structures, contact sites exist between the mtOM and the inner boundary membrane of the mtIM. The mtOM is decorated with numerous voltage-dependent anion channels (VDACs) that are relatively nonspecific for small proteins (<10 kDa). The mtOM is permeable to ions and most metabolites but prevents the leaking of IMS proteins, such as cytochrome c. In contrast, the mtIM is highly selective to ionic exchange and contains metabolite carriers (MC's) and channels that regulate the passage of metabolites and ions between the IMS and the matrix. Protons are pumped out of the matrix and into the IMS generating an ∼0.5–0.7 pH difference between the sides, and thus the IMS carries a positive charge and the matrix a negative charge. The mtIM area is roughly five times larger than the mtOM but the size, shape, and organization of the mtIM varies between mitochondria. The mtIM consists of two types of proton pumps: the primary proton pumps of the respiratory Complexes and the secondary F_oF₁ ATP synthase proton pump. The primary pumps catalyze the transfer of electrons from reducing equivalents, driving protons from the matrix to the IMS, making the matrix relatively more negative than the IMS, and electrically polarizing the mtIM. Polarization of the mtIM establishes the protonmotive force pmF. The respiratory Complexes, including the catalytic components of the ATP synthase, are anchored to the crystal membrane of the mtIM. The matrix also contains discrete microenvironments concentrated with a milieu of proteins, including enzymes of the TCA cycle, metabolites, ribosomes, granules, and mitochondrial DNA (mtDNA).

Figure 2

Overview of the electron transfer system and pathways of oxidative phosphorylation. The cristal membrane of the mitochondrial inner membrane (mtIM) is the primary site of oxidation and reduction reactions within both the electron transfer system (ETS) and oxidative phosphorylation (OXPHOS). The respiratory sequence initiates with oxidation of 3 NADH molecules at Complex I and succinate at Complex II. Of note, depending on the substrate, complete oxidation can yield more than 1 full turn of the tricarboxylic acid (TCA) cycle. Depending on the anaplerotic/cataplerotic status of cycle intermediates, a substrate may not undergo complete oxidation and thus a partial TCA cycle may occur. NADH oxidation to NAD⁺ +H⁺ transfers 2 electrons (e⁻) per NADH through the large Complex resulting in the transfer of 4 protons (H⁺) from the matrix into the intermembrane space (iMS) through Complex I. In contrast, Complex II oxidizes succinate to fumarate, transferring 2e⁻ to bound FAD, yielding FADH₂, which subsequently transfers the electrons to the Q-junction without hydrogen ion pumping. The electrons are passed from Complexes I and II to Q, an electron carrier, which is reduced to QH₂, utilizing protons from the matrix. Electrons are transferred through the nonpolar region of the phospholipid mtIM bilayer to Complex III and protons are released into the iMS. Other membrane-bound structures contribute to net electron transfer in a tissue and organism-specific manner, including glycerol-3-phosphate dehydrogenase (GPD2), the electron transferring flavoprotein dehydrogenase (ETFDH), and proline dehydrogenase (PRODH). The complete transfer of 2 e⁻ from Q through Complex III to cytochrome c requires 2 QH₂ molecules and 2 cytochrome c molecules in a two-step process. 4 H⁺ from both QH₂ molecules are pumped into the IMS and 2 H⁺ from the matrix are used to reform 1 QH₂, resulting in a net proton gradient change of 6 H⁺. Each cytochrome c then transports an electron to Complex IV through the sequential reduction of a copper and heme group, requiring a total of 4 reduced cytochrome c molecules and allowing an oxygen molecule to bind and receive a total of 4e⁻. Additionally, four H⁺ from the matrix are pumped through Complex IV into the IMS and four H⁺ from the matrix are used to form two H₂O, resulting in a net proton gradient change of eight H⁺. The established electrochemical proton gradient between the matrix and the IMS pushes protons through ATP synthase, down the gradient, back into the matrix. With the proton movement, ATP synthase spins and phosphorylates ADP with inorganic phosphate (P_i) to make ATP. However, with increased concentrations of ATP or if respiration is compromised and the pmF falls, the ATP synthase reaction can reverse and hydrolyze ATP to pump protons back out of the matrix to re-establish the pmF. Ultimately the efficiency of the OXPHOS system is influenced by electrochemical gradients, substrate and oxygen concentration, and the integrity of the respiratory Complexes.

Figure 3

Overview of catabolic pathways leading to mitochondrial ATP production. Multiple pathways of substrate oxidation and reduction support energy transfer. Lipids (yellow) are broken down into glycerol backbone and fatty acids; carbohydrates (teal) are broken down into simple sugars and then glucose; and proteins (red) are broken down into monomeric amino acid units. Fatty acids, pyruvate, and many amino acids are transported into the mitochondria and undergo oxidation to fuel the tricarboxylic acid (TCA) cycle. Various metabolic intermediates such glycerol-3-phosphate (G3P) or proline can be transported into the mitochondria to fuel electron transport directly through the oxidative phosphorylation (OXPHOS) system independent of TCA cycle.

Figure 4

Mitochondrial bioenergetic regulation of cancer cell survival and death evasion. Mitochondria confer cancer survival and death evasion through the leveraging of highly plastic, conserved, and interconnected biological processes orchestrated through a dynamic bioenergetic system. Energy transformation through oxidative phosphorylation (OXPHOS) and electron transfer (ET) are dictated by coupling efficiency, the subcellular ADP/ATP ratios, and the availability of reducing equivalents. Redox networks within the mitochondria provide reducing equivalents requisite for energy transformation as well as managing mitochondrial reactive oxygen species (ROS) produced. The mitochondria require ion and molecule transport into the organelle to sustain mitochondrial morphology, driving forces, and functions. Additionally, mitochondria provide molecules and ions to the cancer cell. These metabolic byproducts can highly influence cell fate through molecular signaling cascades generated from the mitochondria.