Mitochondria, cholesterol and cancer cell metabolism

Abstract

Given the role of mitochondria in oxygen consumption, metabolism and cell death regulation, alterations in mitochondrial function or dysregulation of cell death pathways contribute to the genesis and progression of cancer. Cancer cells exhibit an array of metabolic transformations induced by mutations leading to gain-of-function of oncogenes and loss-of-function of tumor suppressor genes that include increased glucose consumption, reduced mitochondrial respiration, increased reactive oxygen species generation and cell death resistance, all of which ensure cancer progression. Cholesterol metabolism is disturbed in cancer cells and supports uncontrolled cell growth. In particular, the accumulation of cholesterol in mitochondria emerges as a molecular component that orchestrates some of these metabolic alterations in cancer cells by impairing mitochondrial function. As a consequence, mitochondrial cholesterol loading in cancer cells may contribute, in part, to the Warburg effect stimulating aerobic glycolysis to meet the energetic demand of proliferating cells, while protecting cancer cells against mitochondrial apoptosis due to changes in mitochondrial membrane dynamics. Further understanding the complexity in the metabolic alterations of cancer cells, mediated largely through alterations in mitochondrial function, may pave the way to identify more efficient strategies for cancer treatment involving the use of small molecules targeting mitochondria, cholesterol homeostasis/trafficking and specific metabolic pathways.

Keywords: Apoptosis; Cholesterol; Mitochondria; Reactive oxygen species; Tumor metabolism; Warburg effect.

Fig. 1

Regulation of HIF1α transcriptional activity. a In normoxia, PHD hydroxylates HIF1α in several proline and asparagine residues, with 2-OG, ascorbate and Fe³⁺, acting as cofactors for the reaction. Hydroxyted HIF1α binds with high affinity to the E3 ubiquitin-ligase pVHL and HIF1α becomes ubiquitinated, marking it for proteasomal degradation. Through this mechanism, HIF1α is kept at very low concentrations and transcriptionally inactive. b In low O₂ conditions, the activity of PHD is inhibited due to lack of oxygen, resulted in no hydroxylation nor ubiquitination of HIF1α. These events lead to the HIF1α protein stabilization which can translocate to the nucleus where it forms a complex with HIF1β and recruits CBP/p300 to the promoter of HIF1α target genes, activating the transcription of a vast array of genes responsible of glycolysis, angiogenesis and cell death resistance which are involved in tumor progression

Fig. 2

Mitochondrial cholesterol-mediated HIF1α stabilization. Mitochondrial cholesterol loading mediated by StARD1 decreases mitochondrial membrane fluidity which leads to an impaired activity of the OGC, which exchanges mitochondrial 2-OG by cytosolic GSH. Cytosolic 2-OG depletion may promote HIF1α stabilization by the impairment of PHD due to their requirement of 2-OG as a cofactor for HIF1α hydroxylation and subsequent degradation. Moreover, 2-OGC inhibition results in mGSH depletion, which in turn, limits the detoxification of ROS, in particular, H₂O₂. The subsequent increase in ROS and oxidative stress impact negatively on PHD, resulting in HIF1α stabilization

Fig. 3

General summary of altered mitochondrial functions in cancer cell life and death. a In normal non-transformed cells glucose is mainly metabolized through the glycolysis pathway and the resulting pyruvate enters the mitochondrial TCA cycle, producing reduced equivalents that are fed into the ETC to generate ATP with high efficiency through the OXPHOS. Antioxidant defenses and coupled respiration through OXPHOS maintain low levels of mitochondrial ROS. b Normal cells are sensitive to apoptotic stimuli triggered by different stresses that finally converge in BAK/BAX activation and MOMP with subsequent release of cytochrome c into the cytosol, stimulating the formation of the apoptosome and apoptotic cell death. c In cancer cells gain-of-function of oncogenes and loss-of-function of tumor suppressor genes (such as MYC, HIF1α and TP53) results in altered metabolism, exemplified by the Warburg effect, characterized by high glucose consumption rates. Glucose is degraded through glycolysis to obtain biosynthetic intermediates and the resulting pyruvate is reduced to lactate to generate ATP. In this scenario, mitochondrial TCA is diverted to generate biosynthetic intermediates, which is accompanied by low OXPHOS activity and increased mitochondrial ROS production. NRF2 is upregulated in cancer cells to counteract ROS and permits cancer cells to withstand its deleterious effects. d Cancer cells, through the overexpression of anti-apoptotic proteins or inactivation of pro-apoptotic proteins, counteract the action of BAX/BAK and evade MOMP formation. Besides this effect, mitochondrial cholesterol loading shields mitochondrial membrane, impairing BAK/BAX oligomerization in MOM and subsequent MOMP formation and represents an additional mechanism of cell death resistance in tumor cells