Cancer metabolism and mitochondria: Finding novel mechanisms to fight tumours

Abstract

Mitochondria are dynamic organelles that have essential metabolic activity and are regarded as signalling hubs with biosynthetic, bioenergetics and signalling functions that orchestrate key biological pathways. However, mitochondria can influence all processes linked to oncogenesis, starting from malignant transformation to metastatic dissemination. In this review, we describe how alterations in the mitochondrial metabolic status contribute to the acquisition of typical malignant traits, discussing the most recent discoveries and the many unanswered questions. We also highlight that expanding our understanding of mitochondrial regulation and function mechanisms in the context of cancer cell metabolism could be an important task in biomedical research, thus offering the possibility of targeting mitochondria for the treatment of cancer.

Keywords: Calcium; Cancer; Metabolism; Mitochondria; ROS.

Fig. 1

Overview of the central role of mitochondria in cell metabolism. Mitochondria, powerhouses of the cell, are regarded as signalling organelles that receive signals from the cytosol and coordinate responses to determinate the cell's fate (see text for further details). "Created with BioRender.com."

Fig. 2

Crosstalk between redox homeostasis and metabolism in cancer cells. Finely tuned reactive oxygen species (ROS) generation and scavenging are two aspects fundamental to cancer cells. Cancer cells are characterized by high levels of ROS that can impact tumour initiation, proliferation, survival and metastasis. To compensate for the higher rate of mitochondrial ROS (mROS) production, tumour cells express high levels of antioxidants to avoid ROS-driven mitochondrial permeability transition (MPT)-regulated cell death. Nrf2: nuclear respiratory factor 2, HIF-1: hypoxia-inducible factor-1. "Created with BioRender.com."

Fig. 3

Mitochondrial enzyme mutations and cancer metabolism. Mutations in enzymes of the TCA cycle or other metabolic pathways as well as components of the electron transport chain alter the metabolome in response to altered mitochondrial metabolism. Mutations in SDH can lead to two different outcomes. The loss of SDH causes succinate accumulation that inhibits PHD, stabilizes HIF1, and inhibits α-KG-dependent histone and DNA demethylases, leading to the activation of proliferative pathways. On the other hand, SDH overexpression can sustain mitochondrial cancer metabolism due to the conversion of succinate into fumarate, which sustains the TCA cycle. Mutations in fumarate hydratase, which increase fumarate concentrations, lead to the inhibition of PHD and histone demethylases, promoting proliferation. Fumarate is also involved in a cysteine post-transcriptional modification, called succination. Isocitrate dehydrogenase (IDH) mutations in cancer help the generation of a neomorphic enzyme that converts isocitrate into 2-hydroxyglutarate (2-HG), a metabolite that exerts its oncogenic effect on PHD and epigenetic regulation. Epigenetic silencing of the urea cycle enzyme argininosuccinate synthase 1 (ASS1) leads to the accumulation of aspartate, which elicits tumorigenesis. SDH: succinate dehydrogenase, PHD: prolyl hydroxylase, HIF-1: hypoxia-inducible factor-1, IDH: isocitrate dehydrogenase, D-2-HG: D-2-hydroxyglutarate, ASS1: argininosuccinate synthase. "Created with BioRender.com."

Fig. 4

Crosstalk between Ca2+ homeostasis and metabolism in cancer cells. Mitochondrial Ca2+can play a dual role in regulating the energetic status of cancer cells. Oncogene activation or tumour suppressor loss modulates ER-mitochondrial Ca2+ transfer to allow escape from apoptosis and resistance to chemotherapy. The mitochondrial calcium uniporter (MCU) complex is composed of the pore-forming subunit MCU (the channel that allows Ca2+ accumulation into the mitochondrial matrix) and its regulators, EMRE and MCUb, all located at the inner mitochondrial membrane (IMM); the mitochondrial calcium uptake (MICU) family members (MICU1–3) are located in the intermembrane space (IMS) and regulate the opening/closing of the complex. The MCU complex can exert both pro- and antineoplastic effects, leading to an altered energetic metabolic status in cancer cells (see text for further details). IMM: inner mitochondrial membrane, MICU: mitochondrial calcium uptake, IMS: intermembrane space, OMM: outer mitochondrial membrane, PTEN: phosphatase and tensin homologue, BAP1: BRCA1-associated protein 1, PML: promyelocytic leukaemia protein; IP3Rs: inositol 1,4,5-trisphosphate receptors, SERCA: sarco-endoplasmic reticulum ATPase, mPTP: mitochondrial permeability transition pore, ER: endoplasmic reticulum, MAMs: mitochondria-associated membranes. "Created with BioRender.com."