Mitochondrial function and energy metabolism in cancer cells: Past overview and future perspectives

Abstract

The involvements of energy metabolism aspects of mitochondrial dysfunction in cancer development, proliferation and possible therapy, have been investigated since Otto Warburg published his hypothesis. The main published material on cancer cell energy metabolism is overviewed and a new unique in vivo experimental approach that may have significant impact in this important field is suggested. The monitoring system provides real time data, reflecting mitochondrial NADH redox state and microcirculation function. This approach of in vivo monitoring of tissue viability could be used to test the efficacy and side effects of new anticancer drugs in animal models. Also, the same technology may enable differentiation between normal and tumor tissues in experimental animals and maybe also in patients.

Introduction

The involvement of the mitochondrion in cancer cell metabolism, functions and therapeutic potential is well documented and accepted. These intracellular organelles have been described by cytologists since the mid 19th century (Lehninger, 1964). According to (Tzagoloff, 1982, Scheffler, 1999), the term mitochondrion was coined by Benda in 1898. However, only in the mid 20th century the role of the mitochondria in oxidative energy metabolism was established in detail (Kennedy and Lehninger, 1949). One of the major fields in cancer research, related to mitochondrial function, was started in the first quarter of the 20th century by Otto Warburg and several other investigators (Cori and Cori, 1925, Crabtree, 1929, Crabtree, 1928). The pioneering work of Warburg between 1923 and 1925 on the metabolism of tumors led to the hypothesis that the development of cancer may originate when cellular glycolysis increases, while mitochondrial respiration becomes impaired (Warburg, 1930, Warburg, 1956a, Warburg, 1956b, Weinhouse, 1956). Warburg’s hypothesis, termed the “Warburg effect,” explains the significance of cellular energy metabolism in the pathophysiology of cancer cells. The Warburg hypothesis was not tested under in vivo conditions while monitoring of mitochondrial function by measuring the NADH redox state for example. Very little attention has been paid, by the “Mitochondrialists,” to Warburg’s work, as can be seen, for example, in the review article by Scheffler (2001a), entitled “A century of mitochondrial research: achievements and perspectives” that does not cite even a single study by Warburg. The significance of energy metabolism in the “come back of the mitochondria” (Scheffler, 2001b) was not discussed. The six hallmarks of cancer cells or tumors, reviewed in 2000 by Hanahan and Weinberg, did not include the bioenergetics of cancer cells, although many publications had dealt with this issue after Warburg’s death in 1970. The validity of Warburg hypothesis was not accepted by various investigators and this issue is still under investigation. For example, Weinhouse in 1956 claimed that “there is no sound experimental basis for the belief that oxidative metabolism in tumors is impaired”. Burk and Schade (1956) support Warburg hypothesis and disagreed with Weinhouse and worte “Respiratory impairment in living cancer cells, first described by Otto Warburg in 1923, is an experimental fact, and not, as described by Weinhouse.” Later on Weinhouse and his collaborators claimed that the high pyruvate kinase activity maybe the main factor leading to the high glycolysis in certain tumors (Gosalvez et al., 1974, Gosalvez et al., 1975, Lo et al., 1968, Weinhouse, 1972). As reported by Garber in 2006, the so-called classical six hallmarks concept was recently challenged by Eyal Gottlieb, claiming that the bioenergetics pattern (aerobic glycolysis) could be the seventh element or hallmark of cancer cells, as described by Warburg 80 years ago. This idea was reviewed recently by Kroemer and Pouyssegur (2008). Very recently Frezza and Gottlieb (2008) reviewed the connection between mitochondrial function and cancer in relation to the “Warburg hypothesis.” They presented two distinct scenarios in which mitochondria play a key role in tumorigenesis. Thompson’s group (Chen et al., 2007, DeBerardinis et al., 2007, DeBerardinis et al., 2008) concluded that “Efforts to integrate modern concepts of signal transduction with cellular metabolism are still in their infancy” and that “One area that needs to be addressed is the regulation of anaplerosis and of mitochondrial metabolism in general.” The same group showed the involvement of glutamine metabolism in transformed cells (DeBerardinis et al., 2008). They found that “transformed tumor cells engage in glutamine metabolism exceeding the need for glutamine as a biosynthetic precursor”. Similar studies by Rossignol et al. (2004) showed that mitochondrial structure and morphology could be modulating by change in energy substrate in cancer cells. McBride et al. (2006) reviewed the other tasks of the mitochondria in addition to the main role in being the powerhouse of all cells in the body.

It is now more than half a century since Chance and Williams published their original work on the mitochondrial metabolic state in vitro (Chance and Williams, 1955b). The discovery of pyridine nucleotides by Harden and Young (1906) a century ago was 30 years later followed by the complete description of their structure by Warburg and collaborators (1935). In 1955, the groundbreaking study of Chance and Williams (1955a) defined for the first time the metabolic states of isolated mitochondria in vitro, and correlated these states to the oxidation–reduction levels of respiratory enzymes including the NADH.

Nearly 1000 relevant publications have appeared since the initial studies of NADH fluorescence in vitro and, most importantly, in vivo (Chance et al., 1962, Chance and Williams, 1955c). Several key experiments have shown that this technique could be used for the metabolic mapping of the animal brain as well as other organs. More recently, this methodology was adapted for clinical applications (in intra-operative and intensive care units). Over the past half century, NADH redox state monitoring has been researched in vitro and in vivo, including its clinical applications that have become practical in the last few years (Deutsch et al., 2004, Mayevsky et al., 1996, Mayevsky et al., 2004, Mayevsky et al., 2005, Mayevsky and Rogatsky, 2007). This approach could now be used to investigate the validity of the so-called “Warburg effect” under in vivo monitoring of tissue vitality. It is possible to monitor the mitochondrial NADH in vivo, together with the microcirculatory blood flow, hemoglobin oxygenation and blood volume in various animal tumor models. This will enable the researchers to test the safety and efficacy of various anticancer drugs using in vivo tumor models. The aims of this paper are to present a very general review on cancer cell and tumor energy metabolism as an introduction to the proposal to use a new tissue monitoring approach for studying the safety and efficacy of new anticancer drugs. The same monitoring approach may and could be developed and used, in the future, as a diagnostic tool for clinical practice as well.