Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

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: cancer therapy; metabolic network; metabolic rewiring; mitochondria; targeting mitochondria.

Figure 1

Mitochondrial relevance to cancer progression. Mitochondria play an important role in the main processes that characterize tumor progression. The figure shows the main effects of mitochondria in the three main steps characterizing cancer development: (a) ROS production is capable of causing damage at the levels of nuclear and mitochondrial DNA, thus promoting oncogenesis; (b) metabolic plasticity is responsible for greater tumor progression and stemness; (c) biogenesis and high mitochondrial turnover are responsible for EMT and metastatic dissemination.

Figure 2

OXPHOS as promising target to affect mitochondrial activity in cancer cells. ETC complexes, exploiting the oxidation of NADH and FADH₂ from TCA and glycolysis, generate an electrochemical gradient able to determine ATP production through F₁F_O-ATPase. In the figure: the different components of the ETC, the F1Fo-ATPase, and the molecules discussed in this review, which have exhibited promising results in vitro and in vivo in inhibiting their respective targets, are depicted in detail.

Figure 3

Targeting heme flux in cancer cells. The figure schematically shows heme uptake and biosynthesis, as well as its incorporotation into complexes II, III, and IV of the electron transport chain. The major heme flux inhibitors discussed in this review and their targets are shown.

Figure 4

Targeting TCA and glutaminolysis in cancer cells. Glutaminolysis supplies the TCA cycle with anabolic intermediates to sustain a high proliferate rate in cancer cells. The figure shows the main stages of TCA and glutaminolysis inhibited by the molecules discussed in this review, which have displayed promising results in vitro and in vivo.

Figure 5

Targeting mitochondrial biogenesis. High mitochondrial efficiency, necessary to ensure a high proliferation and stemness, is guaranteed by high biogenesis, turnover, and mitochondrial dynamics. The figure shows the level at which the different molecules discussed in this review modulate mitochondrial protein expression (at transcriptional and translational level) as well as mitochondrial dynamics.