Glycolysis has long been considered as the major metabolic process for energy production and anabolic growth in cancer cells. Although such a view has been instrumental for the development of powerful imaging tools that are still used in the clinics, it is now clear that mitochondria play a key role in oncogenesis. Besides exerting central bioenergetic functions, mitochondria provide indeed building blocks for tumor anabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and govern cell death. Thus, mitochondria constitute promising targets for the development of novel anticancer agents. However, tumors arise, progress, and respond to therapy in the context of an intimate crosstalk with the host immune system, and many immunological functions rely on intact mitochondrial metabolism. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.

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Mitochondrial metabolism and cancer.

Calcium ions (Ca2+) are some of the most versatile signalling molecules, and they have many physiological functions, prominently including muscle contraction, neuronal excitability, cell migration and cell growth. By sequestering and releasing Ca2+, mitochondria serve as important regulators of cellular Ca2+. Mitochondrial Ca2+ also has other important functions, such as regulation of mitochondrial metabolism, ATP production and cell death. In recent years, identification of the molecular machinery regulating mitochondrial Ca2+ accumulation and efflux has expanded the number of (patho)physiological conditions that rely on mitochondrial Ca2+ homeostasis. Thus, expanding the understanding of the mechanisms of mitochondrial Ca2+ regulation and function in different cell types is an important task in biomedical research, which offers the possibility of targeting mitochondrial Ca2+ machinery for the treatment of several disorders.

The machineries, regulation and cellular functions of mitochondrial calcium.

Hypoxia triggers several mechanisms to adapt cells to a low oxygen environment. Mitochondria are major consumers of oxygen and a potential source of reactive oxygen species (ROS). In response to hypoxia they exchange or modify distinct subunits of the respiratory chain and adjust their metabolism, especially lowering the citric acid cycle. Intermediates of the citric acid cycle participate in regulating hypoxia inducible factors (HIF), the key mediators of adaptation to hypoxia. Here we summarize how hypoxia conditions mitochondria with consequences for ROS-production and the HIF-pathway.

Mitochondrial composition and function under the control of hypoxia.

Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease.

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Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

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NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential.

Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.

https://tandfonline.com/doi/pdf/10.1080/15548627.2016.1166318

Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.

Mitochondrial Ca2+ signaling, which is strongly dependent on the mitochondrial Ca2+ uniporter (MCU) complex, has a series of key roles in physiopathological processes, including energy metabolism, reactive oxygen species (ROS) production and cell apoptosis. However, a mechanistic understanding of how the mitochondrial Ca2+ signaling is remodeled and its functional roles remains greatly limited in cancers, especially in hepatocellular carcinoma. Here we demonstrated that the MCU complex was dysregulated in hepatocellular carcinoma (HCC) cells and significantly correlated with metastasis and poor prognosis of HCC patients. Upregulation of MCU clearly enhanced the Ca2+ uptake into mitochondria, which significantly promoted ROS production by downregulating nicotinamide adenine dinucleotide+ (NAD+)/reduced form of nicotinamide adenine dinucleotid (NADH) ratio and the NAD+-dependent deacetylase activity of sirtuin 3 to inhibit superoxide dismutase 2 (SOD2) activity. Moreover, our data indicated that the MCU-dependent mitochondrial Ca2+ uptake promotes matrix metalloproteinase-2 activity and cell motility by ROS-activated c-Jun N-terminal kinase pathway, and thus contributed to the increased ability of invasion and migration in vitro and intrahepatic and distal lung metastasis in vivo of HCC cells. In addition, treatment with the mitochondrial Ca2+-buffering protein parvalbumin significantly suppressed ROS production and the ability of HCC metastasis. Our study uncovers a mechanism that links the remodeling of mitochondrial Ca2+ homeostasis to ROS production, and provides evidence supporting a metastasis-promoting role for the MCU-dependent mitochondrial Ca2+ uptake in HCC. Our findings suggest that the mitochondrial Ca2+ uptake machinery may potentially be a novel therapeutic target for HCC metastasis.

MCU-dependent mitochondrial Ca 2+ inhibits NAD +/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells

Aims: Levels of the mitochondrial calcium uniporter regulator 1 (MCUR1) increases during development of hepatocellular carcinoma (HCC). However, mechanisms of how mitochondrial Ca2+ homeostasis is modulated and its function remain limited in cancers. Results: MCUR1 was frequently upregulated in HCC cells to enhance the Ca2+ uptake into mitochondria in an MCU-dependent manner, which significantly facilitated cell survival by inhibiting mitochondria-dependent intrinsic apoptosis and promoting proliferation of HCC cells, and thus led to poor prognosis. In vivo assay confirmed these results, indicating that overexpressed MCUR1 notably decreased the fraction of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and increased the positive Ki67 staining in xenograft tumors, while reduced MCUR1 expression was associated with impaired growth capacity of HCC cells in nude mice. The survival advantage conferred by MCUR1-mediated mitochondrial Ca2+ uptake was majorly caused b...

MCUR1-Mediated Mitochondrial Calcium Signaling Facilitates Cell Survival of Hepatocellular Carcinoma via Reactive Oxygen Species-Dependent P53 Degradation.

Lele Ji

Papers

Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.

MCU-dependent mitochondrial Ca 2+ inhibits NAD +/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells

MCUR1-Mediated Mitochondrial Calcium Signaling Facilitates Cell Survival of Hepatocellular Carcinoma via Reactive Oxygen Species-Dependent P53 Degradation.