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Although previously it was considered that cancer cells had high glycolysis and mitochondrial impairment, recent evidence has revealed that several events during tumorigenesis such as chemoresistance and metastasis are dependent on mitochondrial function. This converts mitochondria into a promising target for new anticancer strategies. In this chapter, we analyzed selected examples of natural products (NPs) isolated from diverse sources such as bacteria, fungi, marine sponges, plants, and snake venom that promote cell death and inhibition of the proliferation and migration/invasion of malignant cells through the induction of mitochondrial dysfunction. Some of them act directly inhibiting oxidative phosphorylation by (1) interaction with respiratory complexes and other ones affect indirectly the oxidative phosphorylation by (2) modulating the mitochondrial Ca2+ uptake, (3) controlling the glucose-derived pyruvate oxidation by modulation of PDK/PDH axis, (4) disrupting the inner mitochondrial membrane integrity and fluidity by interaction with cardiolipin, or (5) promoting changes in the quality control of mitochondria. Several NP derivatives that incorporate a triphenylphosphonium cation as a mitochondrial drug delivery system have been described whose anticancer effects occur by inhibitions of Complex I, oxoglutarate dehydrogenase, thioredoxin reductase, ATP synthase, and mitochondrial potassium Kv1.3 channel. The recent advances in the mechanisms of action of natural compounds that inhibit the proliferation of cancer stem cells, a relevant type of tumor-initiating cells involved in the chemoresistance and tumor relapse, are discussed in detail. Notably, NPs offer the opportunity to discover innovative chemical structures and unexpected mechanisms of action on cancer mitochondrial bioenergetics with promising anticancer approaches.

A simple mechanism to understand the biological activity of a series of hydroquinone derivatives is proposed. To validate this proposition Gibbs free energies of formation of the different species involved were calculated. The calculations were performed using density functional theory (DFT) at B3LYP/6-31++G(2df,p) level of theory, including solvation effect. The results show that two important variables to examine are the equilibrium phenol-phenoxide and the solvation energy of neutral species, since the balance between both variables affects the capability of the molecules to cross membranes. Once the molecule crossed the membrane, the formation of radical species shows a qualitative correlation with the magnitude of IC 50 values. This provides a reasonable criterion to search for more efficient anticancer drug.

Tumor cells present a known metabolic reprogramming, which makes them more susceptible for a selective cellular death by modifying its mitochondrial bioenergetics. Anticancer action of the antioxidant 9,10-dihydroxy-4,4-dimethyl-5,8-dihydroanthracen-1(4H)-one (HQ) on mouse mammary adenocarcinoma TA3, and its multiresistant variant TA3-MTXR, were evaluated. HQ decreased the viability of both tumor cells, affecting slightly mammary epithelial cells. This hydroquinone blocked the electron flow through the NADH dehydrogenase (Complex I), leading to ADP-stimulated oxygen consumption inhibition, transmembrane potential dissipation and cellular ATP level decrease, without increasing ROS production. Duroquinol, an electron donor at CoQ level, reversed the decrease of cell viability induced by HQ. Additionally, HQ selectively induced G₂/M-phase arrest. Taken together, our results suggest that the bioenergetic dysfunction provoked by HQ is implicated in its anticancer action.