International Journal of Molecular Sciences Review Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment Luca Frattaruolo y , Matteo Brindisi y , Rosita Curcio, Federica Marra, Vincenza Dolce and Anna Rita Cappello * Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Rende (CS), Italy; [email protected] (L.F.); [email protected] (M.B.); [email protected] (R.C.); [email protected] (F.M.); [email protected] (V.D.) * Correspondence: [email protected] These authors contributed equally and should be considered co-first authors. y Received: 31 July 2020; Accepted: 19 August 2020; Published: 21 August 2020 Abstract: Metabolic reprogramming is a hallmark of cancer, which implements a profound metabolic rewiring in order to support a high proliferation rate and to ensure cell survival in its complex microenvironment. Although initial studies considered glycolysis as a crucial metabolic pathway in tumor metabolism reprogramming (i.e., the Warburg effect), recently, the critical role of mitochondria in oncogenesis, tumor progression, and neoplastic dissemination has emerged. In this report, we examined the main mitochondrial metabolic pathways that are altered in cancer, which play key roles in the different stages of tumor progression. Furthermore, we reviewed the function of important molecules inhibiting the main mitochondrial metabolic processes, which have been proven to be promising anticancer candidates in recent years. In particular, inhibitors of oxidative phosphorylation (OXPHOS), heme flux, the tricarboxylic acid cycle (TCA), glutaminolysis, mitochondrial dynamics, and biogenesis are discussed. The examined mitochondrial metabolic network inhibitors have produced interesting results in both preclinical and clinical studies, advancing cancer research and emphasizing that mitochondrial targeting may represent an effective anticancer strategy. Keywords: mitochondria; metabolic rewiring; metabolic network; targeting mitochondria; cancer therapy 1. Mitochondria and Cancer For many years, glycolysis has been considered the engine of cancer cells, the metabolic pathway that ensures their rapid production of ATP and supports an uncontrolled proliferation. Indeed, the Warburg studies showed that cancer metabolic reprogramming shifts energy metabolism towards the glycolytic pathway even in aerobic conditions [1]. Such aerobic glycolysis conditions, defined as the Warburg effect, ensures a rapid production of ATP from glucose, albeit less efficiently than complete mitochondrial oxidation, a process coupled with oxidative phosphorylation. The maintenance of the glycolytic pathway in cancer is associated with the conversion of the high amount of produced pyruvate into lactate, in order to guarantee a high NAD+/NADH cell ratio, which is essential for feeding glycolysis. The clinical application of the Warburg effect has led to the development of imaging technologies allowing the identification of malignant neoplasms by evaluating the ability of cells to metabolize 2-[18F] fluoro-2-deoxy-d-glucose (18F-FDG), a glucose analogue easily traceable by positron emission tomography (PET). Based on Warburg’s observations, for a long time, aerobic glycolysis of cancer cells was believed to be the result of a mitochondrial dysfunction, which in turn was considered to be a cause of cancer. Numerous nuclear–cytoplasmic transfer experiments supported this theory, showing that normal Int. J. Mol. Sci. 2020, 21, 6014; doi:10.3390/ijms21176014 www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci. Sci.2020 2020,,21 21,, 6014 x FOR PEER REVIEW 22 of of 21 21 Numerous nuclear–cytoplasmic transfer experiments supported this theory, showing that normal cytoplasm suppresses tumorigenesis in cell cybrids [2]. In particular, several in vitro and in vivo cytoplasm suppresses tumorigenesis in cell cybrids [2]. In particular, several in vitro and in vivo studies showed that the fusion of healthy enucleated cells (cytoplasts) with tumoral karyoplastes can studies showed that the fusion of healthy enucleated cells (cytoplasts) with tumoral karyoplastes can significantly reduce tumorogenicity with respect to parental cancer. In contrast, the fusion of tumor significantly reduce tumorogenicity with respect to parental cancer. In contrast, the fusion of tumor cytoplasts with healthy karyoplasts does not determine any reduction of tumorogenicity, suggesting cytoplasts with healthy karyoplasts does not determine any reduction of tumorogenicity, suggesting that tumor development is triggered by mitochondrial rather than nuclear dysfunctions. that tumor development is triggered by mitochondrial rather than nuclear dysfunctions. In recent decades, however, the Warburg effect has been overcome as the dogma of In recent decades, however, the Warburg effect has been overcome as the dogma of cancer cancer biochemistry, with hypotheses emerging that the mechanisms underlying tumor metabolic biochemistry, with hypotheses emerging that the mechanisms underlying tumor metabolic reprogramming are much more complex than those theorized by Warburg, and that mitochondrial reprogramming are much more complex than those theorized by Warburg, and that mitochondrial metabolism can change during oncological pathology, thus influencing neoplastic transformation, metabolism can change during oncological pathology, thus influencing neoplastic transformation, tumortumor progression, progression, and and metastatic metastatic dissemination dissemination processes processes (Figure (Figure1). 1). FigureFigure 1.1. MitochondrialMitochondrial relevance relevance to to cancer cancer progression. progression. Mitochondria Mitochondria play play an important an important role in role the inmain the mainprocesses processes that thatcharacterize characterize tumor tumor progre progression.ssion. The The figure figure shows shows the the main main eeffectsffects ofof mitochondriamitochondria in in the the three three main main steps steps characterizing characterizing cancer cancer development: development: (a) ROS (a production) ROS production is capable is ofcapable causing of damage causing at damage the levels at ofthe nuclear levels andof nuclear mitochondrial and mitochondrial DNA, thus promoting DNA, thus oncogenesis; promoting (boncogenesis;) metabolic plasticity(b) metabolic is responsible plasticity foris responsible greater tumor for progression greater tumor and progression stemness; (c and) biogenesis stemness; and (c) highbiogenesis mitochondrial and high turnover mitochondrial are responsible turnover for are EMT responsible and metastatic for EMT dissemination. and metastatic dissemination. MitochondrialMitochondrial metabolismmetabolism playsplays aa keykey initialinitial role role during during oncogenesis. oncogenesis. AA lotlot ofof studiesstudies havehave highlightedhighlighted thatthat thethe mitochondrialmitochondrial generationgeneration ofof reactivereactive oxygenoxygen speciesspecies (ROS),(ROS), subproductssubproducts ofof respiration,respiration, favors favors DNA DNA damage. damage. ThisThis cancan resultresult in in mutagenesis mutagenesis able able to to a affectffect proto-oncogenes proto-oncogenes and and tumor-suppressortumor-suppressor genes,genes, leadingleading toto self-feedingself-feeding tumortumor proliferationproliferation [3[3].]. InIn thisthis regard,regard, inin manymany tumors,tumors, anan increaseincrease inin ROS ROS production production has has been been related related to to mutations mutations found found in in the the mitochondrial mitochondrial DNADNA (mtDNA), (mtDNA), encoding encoding for for several several subunits subunits constituting constituting the the electron electron transport transport chain chain complexes complexes [4]. Over[4]. Over the years,the years, in addition in addition to ROS,to ROS, other other metabolites, metabolites, intermediates intermediates of of mitochondrial mitochondrial metabolism, metabolism, havehave been been believed believed to triggerto trigger oncogenesis oncogenesis and neoplastic and neoplastic transformation transformation processes, processes, and these moleculesand these havemolecules been definedhave been as oncometabolitesdefined as oncometabolites [5–7]. In particular, [5–7]. In anparticular, accumulation an accumulation of succinate, of fumarate,succinate, andfumarate, 2-hydroxy-glutarate and 2-hydroxy-glutarate (2-HG) has (2-HG) been found has been in several found tumors.in several The tumors. accumulation The accumulation of succinate of andsuccinate fumarate and is fumarate mainly driven is mainly by inactivating driven by mutations inactivating concerning mutations the succinateconcerning dehydrogenase the succinate (SDH)dehydrogenase and fumarate (SDH) hydratase and fumarate (FH) enzymes, hydratase respectively. (FH) enzymes, These respectively. mutated enzymes, These mutated in their enzymes, inactive in their inactive forms, do not allow the normal progression of TCA cycle which, in turn, induces the Int. J. Mol. Sci. 2020, 21, 6014 3 of 21 forms, do not allow the normal progression of TCA cycle which, in turn, induces the accumulation of their specific substrates. On the other hand, the accumulation of 2-HG is due to mutations found in the isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2), which are normally responsible for converting isocitrate into α-keto-glutarate (α-KG). When IDH1 and IDH2 are mutated, a strong accumulation of 2-HG is observed in the presence