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Abstract

Background

Abnormalities in mitochondrial structure or function are closely related to the development of malignant tumors. Mitochondrial metabolic reprogramming provides precursor substances and energy for the vital activities of tumor cells, so that cancer cells can rapidly adapt to the unfavorable environment of hypoxia and nutrient deficiency. Mitochondria can enable tumor cells to gain the ability to proliferate, escape immune responses, and develop drug resistance by altering constitutive junctions, oxidative phosphorylation, oxidative stress, and mitochondrial subcellular relocalization. This greatly reduces the rate of effective clinical control of tumors.

Purpose

Explore the major role of mitochondria in cancer, as well as targeted mitochondrial therapies and mitochondria-associated markers.

Conclusions

This review provides a comprehensive analysis of the various aspects of mitochondrial aberrations and addresses drugs that target mitochondrial therapy, providing a basis for clinical mitochondria-targeted anti-tumor therapy.

Keywords

cancer mitochondrial dysfunction metabolic reprogramming mitochondria-targeting immune microenvironment

Introduction

Cancer is a major challenge facing the world today, posing a serious health and socioeconomic burden on humanity. According to the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, the global cancer burden is expected to be 28.4 million cases in 2040, a 47% increase from 2020.¹ Deepening our understanding of cancer pathogenesis and exploring more effective therapeutic strategies have become important directions of current cancer research.

Mitochondria are one of the most important organelles in the human body and the only organelles other than the nucleus that have DNA.² Mitochondria are involved in and regulate a variety of biological processes, such as cellular energy production, redox reactions, signaling, biosynthesis, and apoptosis. They are essential for maintaining normal cellular and bodily functions.^3-5

Recent studies have shown that mitochondrial dysfunction due to defective tricarboxylic acid cycle (TCA) enzymes, mutations in mitochondrial DNA genes, defects in the mitochondrial electron transport chain, and mitochondrial dysfunction in the tumor microenvironment due to oxidative stress, aberrant oncogenes, and tumor suppressor signaling, plays an important role in tumor growth, metastasis, immune evasion, chemotherapeutic resistance, and prognosis.^2,6-10 In addition, shifts in intercellular mitochondrial levels promote tumor metabolic reprogramming.¹¹ Therefore, a comprehensive understanding of the association between mitochondria and tumors is essential for elucidating tumor pathogenesis, diagnosis, treatment, and prognosis assessment.

Relationship Between Mitochondria and Cancer

Mitochondrial and Energy Metabolism Reprogramming in Cancer Cells

Glucose is the main source of energy in normal cells. Glucose in the cytoplasm is converted to pyruvate via the glycolytic pathway. Pyruvate then enters the mitochondria for oxidative phosphorylation to produce a large amount of ATP, providing energy for various cellular activities and maintaining cellular energy homeostasis.^12,13 In contrast, malignant tumor cells usually show an increased dependence on glycolysis.¹⁴ The main reason may be that the rapid and unlimited proliferation and distant metastasis of cancer cells and other activities demand a high synthesis of macromolecular precursors for life activities and energy, which is difficult to meet by the normal oxidative phosphorylation pathway.¹⁵ In addition, the tumor microenvironment is usually hypoxic. Cancer cells induce a series of adaptive changes in mitochondria, reprogramming metabolic pathways, selecting glycolytic pathways, and optimizing the rate of energy production and the supply of biosynthetic precursors to achieve a rapid adaptation to the unfavorable environment of hypoxia and lack of nutrients and satisfy the needs of the rapid proliferation of their cancer cells.^16,17 Patients with endometrial cancer are at high risk of recurrence and metastasis, with a 5-year survival rate of less than 20%.¹⁸ Su,¹⁹ Mao²⁰ et al demonstrated that overexpression of estrogen-related receptor α promotes endometrial invasion and metastasis by inducing glycolysis through NLRP3-dependent manner.

Indeed, mitochondrial metabolism is complex and plastic. This property allows cancer cell subpopulations to switch between glycolysis and oxidative phosphorylation to support their bioenergetic needs and, ultimately, various processes such as growth, invasion, immune escape, and drug resistance generation.^21-23

Subpopulations of tumor cells that are dormant after oncogene ablation have properties of cancer stem cells, which are dependent on OXPHOS for survival, and these cells are responsible for tumor recurrence. An analysis based on transcriptome sequencing data from pancreatic ductal adenocarcinomas by Andrea et al revealed a strong dependence of such cells on mitochondrial respiration and a reduced dependence on glycolysis for cellular energetics.24 Intracellular energy metabolism is reprogrammed to mitochondrial oxidative phosphorylation in an autophagy-dependent manner after glycolysis inhibition in multiple types of tumor cells to ensure cell survival.25 CSCs are less glycolytic, produce less reactive oxygen species (ROS), and maintain higher levels of ATP compared to bulk tumors. In addition, mitochondrial mass and membrane potential are increased in CSCs, reflecting enhanced mitochondrial function and an increased rate of oxygen consumption compared to bulk tumors, which produce energy primarily through glycolysis.23 Such changes have been found in glioblastoma and ovarian cancer.26,27 Enhanced oxidative phosphorylation is required for cancer cell metastasis, whereas increased inhibition of glycolysis is required for cancer cell growth, metastasis, and avoidance of cell death. Similar effects have been observed in pancreatic cancer.28 This suggests that mitochondrial metabolism may be a compensatory pathway for energy production in the presence of insufficient glycolysis.

In addition, some types of cancer cells have an increased dependence on certain processes related to mitochondrial metabolism. For example, the isocitrate carrier SLC25A1 is the only known human citrate transporter protein in mitochondrial membranes and plays a major regulatory role in lipid metabolism.29 There is evidence that, compared to normal samples, colorectal cancer (CRC) tumor samples showed significantly elevated expression of SLC25A1, which exerts a dual regulatory role in the reprogramming energy metabolism. SLC25A1 promotes CRC growth under normal conditions by increasing lipid synthesis and protects CRC cells from energy stress-induced apoptosis by increasing oxidative phosphorylation.30 Interestingly, the antitumor effects of miR-195 overexpression are mediated by impairing mitochondrial function, thereby further modulating mitochondrial dynamics.31

The tumor suppressor p53 protein is a key metabolic regulator that plays a critical role in maintaining cellular metabolic homeostasis and mitochondrial function.³² P53 controls glutamine metabolism by regulating mitochondrial metabolism to activate the glutaminase GLS2. It inhibits the glycolytic process by downregulating the expression of glucose transport proteins through the NF-κB signaling pathway and upregulating the expression of TP53-induced glycolysis-regulating phosphatases. P53 promotes mitochondrial synthesis and division, maintains mitochondrial genome integrity, and ensures mitochondrial quality control and turnover, thus ensuring normal mitochondrial function.^32,33 Hidekazu et al³⁴ showed that DPYSL4 acts as a p53-inducible regulator of energy metabolism in cancer and normal cells, binds to the mitochondrial supercomplex, counteracts the effects of the Warburg effect, and affects mitochondrial function and metabolic pathways, thus exerting an inhibitory effect on tumor cell growth. Investigating the role of mitochondria in energy metabolism in cancer cells could provide a basis for the development of therapeutic strategies that target metabolic pathways specific to cancer cells.

Effect of Mitochondria on Tumor Cell Viability

Mitochondria can regulate tumor cell proliferation, death, and invasion by promoting oxidative phosphorylation, subcellular relocalization of mitochondria, and other mechanisms.³⁵ Durrant and Morrison³⁶ studied Raf protein kinase, a key intermediate in cell signaling that acts directly on the Ras GTPase and serves as an initiating kinase for the ERK cascade reaction. In tumors, Raf activation leads to altered mitochondrial function, which affects tumor cell proliferation. Activation of Raf is reportedly associated with changes in its conformation that require adjustments to its internal structure so that the N- and C-termini of the kinase domain are connected by a flexible hinge region. These changes promote the formation of Raf dimers, which in turn affect tumor cell proliferation.

The role of mitochondria in cell death is thought to be relevant to cancer development. Apoptosis acts as a protective mechanism to inhibit tumor growth and eliminate nascent cancer cells. Elevation of reactive oxygen species (ROS) levels is a major mechanism that triggers apoptosis in cancer cells due to increased metabolic activity. Ca²⁺ overload and ROS-triggered high-conductance channel-induced pore formation in the endosomal membranes, that is, the mitochondrial permeability transition, further activate the endogenous apoptotic pathway.^37,38 Huang³⁹ et al find that the non-psychoactive phytocannabinoid cannabidiol (CBD) promotes mitochondrial autophagy by inducing calcium in-flow through activation of TRPV4 (transient receptor potential cation channel subfamily V member 4). Combined treatment with CBD and temozolomide also demonstrated control of tumor size and improved survival in patient-derived neurosphere cultures and in situ models in mice. Furthermore, membrane depolarization is a critical event in the activation of TRAIL, a ligand that causes mitochondrial fragmentation in a variety of human cancer cell lines. This ligand ultimately induces apoptosis and necrotic cell death through the activation of CASP family members and RIPK1/RIPK3, respectively. Excess ROS can also trigger necrotic cell death via RIPK1 oxidation and promotion of necrosome complex formation, subsequently triggering inflammatory and anti-cancer immune responses.³⁸ In addition, several anti-apoptotic factors, including the Bcl-2 family of proteins, can prevent cell death by stabilizing the integrity of the outer mitochondrial membrane and blocking apoptotic signaling.^40,41

The presence of mitochondrial survivin and Hsp90 hapten contributes to the correct folding of the oxidative phosphorylation complex II subunit. This allows mitochondria to migrate to the tumor cell’s cortical cytoskeleton with regional energy support, allowing tumor cells to metastasize and spread in vivo.^12,42 Actin filaments constitute a channel for short-distance mitochondrial transport.⁴³ MYO6, a marker for ovarian cancer, causes F-actin cages to accumulate around mitochondria that function abnormally and serve to inhibit mitochondrial subcellular relocalization, thereby promoting tumor cell death.⁴⁴ Tumor cells can also actively acquire mitochondria from immune cells via nanomicro systems, allowing for rapid cancer cell growth and immune depletion.^45,46

Mitochondrial Dysfunction and Oxidative Stress

Mitochondria play an essential role in maintaining the intracellular redox balance and responding to oxidative stress. Oxidative stress can lead to DNA damage and promote cancer development and immune escape.^47-49

ROS stress can stimulate cancer cells to secrete inflammatory factors such as IL-6, IFN-γ, TGFβ, VEGF, IL-4, and IL-10. These factors can inhibit the function of immune cells and allow cancer cells to escape the immune system’s attack. They can also promote cancer cell survival, transformation, and metastasis.⁴⁸ Aging, environmental toxins, and drug toxicity cause mitochondrial dysregulation and increase ROS production. This damages mitochondrial DNA (mtDNA) and proteins and stimulates the production of more ROS, creating a vicious cycle.^48,50

ROS produced by mitochondria can promote both survival and inflammatory responses in cancer cells. They can also lead to immunosuppression, which allows cancer cells to evade clearance by the immune system and promote cancer cell survival and metastasis.⁴⁸ Oxidative stress promotes the escape of damaged mtDNA to the cytoplasm, upregulates the expression of interferon-stimulated genes (ISGs), and activates the interferon signaling pathway.^51-53 ROS may further damage mtDNA and promote immune escape through the stimulator of interferon genes (STING)-interferon-programmed cell death-ligand 1 (PD-L1) signaling pathway.⁵¹ In addition, ROS may enhance the secretion of NF-κB-dependent inflammatory cytokines to suppress the anti-tumor functions of macrophages, dendritic cells, and T cells.⁴⁸ ROS may also contribute to enhanced antigen presentation, upregulation of the immune response, and reduction of immune escape. Many studies have emphasized the dual nature of ROS in cancer, both as promoters of cancer growth and as potential therapeutic targets. Prodrugs responsive to ROS have been suggested to improve the effectiveness of cancer treatment.^54,55 Modulation of ROS may have translational and clinical significance in enhancing the efficacy of cancer immunotherapy.⁵⁶

Point mutations, insertions, mass deletions, and copy number variations in mtDNA are present in different types of cancer.⁵⁷ These mtDNA alterations increase oxidative stress, lead to mitochondrial dysfunction, and affect patient prognosis. For example, in adrenocortical carcinomas and low-grade gliomas, lower tumor mtDNA levels are associated with poorer survival rates.⁵⁸ Specific mtDNA mutations promote tumor growth and malignant progression of cancer by increasing ROS output and preventing apoptosis.⁵⁷ In response to this, cancer cells initiate a mechanism known as the mitochondrial stress response, which drives tumor progression by repairing the structure and function of mitochondria and preventing cell death.⁵⁰

In addition, mitochondria undergo dynamic changes such as fission and fusion. Mitochondrial fission promotes cancer progression, whereas mitochondrial fusion reduces metabolic stress and maintains mitochondrial function. In cancer cells, mitochondrial fission is associated with various factors that can lead to DNA damage and apoptosis. For example, in pancreatic cancer, mutations in the KRAS gene promote mitochondrial fission and activation of DRP1, causing further cancer progression.⁵⁷ If the balance of mitochondrial fission and fusion is dysregulated, the cell’s anti-apoptotic mechanisms and ROS production will be affected, further promoting tumor cells’ invasiveness and metastatic ability.^59,60

Mitochondria in the Tumor Microenvironment

Alterations in the microenvironment, such as hypoxia, acidic pH, and other changes, may lead to the development of malignancies associated with epigenetic and metabolic alterations that promote tumor invasion and metastasis.^61,62 The tumor microenvironment not only provides the necessary supply of nutrients and oxygen to promote tumor growth but also regulates the behavior of tumor cells through intercellular communication and influences the immune system’s response, which in turn affects tumor metastasis and response to therapy.^63,64

In addition to their fundamental roles in metabolic processes and energy production, mitochondria promote cancer growth and spread by altering the tumor microenvironment. This reveals that mitochondria are not only the center of energy production but also a key factor in regulating tumor behavior. A study by Delaunay et al⁶⁵ found that tumor cells that do not undergo cell division and are dependent on CD36, a type of tumor cell that initiates metastasis, rely on mitochondrial m5C modifications to enhance their ability of tumor cells to spread and invade. This suggests the possibility of interrupting the metabolic adaptations of tumor cells by interfering with mitochondrial mRNA translation, which could potentially prevent tumor spread. The interaction between mitochondria and immune cells in the tumor microenvironment is equally important for enhancing therapeutic efficacy. Liu et al⁶⁶ highlighted the decisive role of mitochondria in regulating T-cell fate and function in the tumor microenvironment, showing that mitochondrial reprogramming leads to the functional depletion of T cells in the tumor microenvironment, which weakens the immune response to the tumor. Dong et al constructed a nuclear mitochondria-related gene prognostic model for pancreatic cancer based on 1930 nuclear mitochondria-related genes. They found that in the tumor immune microenvironment of pancreatic cancer, most immune cells, except for type II helper T cells, infiltrated to a lesser extent in the high-risk than in the low-risk group and that, for the high-risk group, immune checkpoints against CD274, HAVCR2, and SIGLEC15 inhibitors may play a role in the high-risk group. Purposeful removal of certain types of immunosuppressive cells, such as regulatory T cells and M2-type macrophages, may increase efficacy in the low-risk group.⁶⁷ This suggests that mitochondria are not only the center of energy production but also a key factor in regulating tumor behavior. Therefore, an in-depth understanding of how mitochondrial function affects biological processes within cancer cells and its role in promoting immune escape mechanisms is crucial for the development of effective immunotherapeutic strategies.

Mitochondrial Transfer and Cancer Proliferation

Cells preferentially use their mitochondria for energy metabolism. This can be horizontally inherited through genealogical inheritance, extracellular vesicles (EVs), tunneling nanotubes (TNTs), and other mechanisms.⁶⁸ Mitochondria can be localized to areas of high energy demand to provide energy for cellular activities. When mitochondria do not provide enough energy to meet metabolic needs, such as in cancer, “imported” mitochondria, that is, horizontal movement of mitochondria, occur. Mitochondria-free cancer cells divide slowly. To achieve rapid proliferation, tumor cells acquire mitochondria from co-cultured cells.^69,70 This phenomenon has been observed in in vitro experiments with breast cancer cells and osteosarcoma cells.^11,71,72 In addition, different cancer cells acquire mitochondria from various sources depending on the tumor microenvironment. For example, acute myeloid leukemia cells and glioma cells can obtain mitochondria from the corresponding mesenchymal stem cells.^73,74 Prostate cancer cells can acquire mitochondria from tumor-associated fibroblasts.⁷⁵ Human breast cancer cells can acquire mitochondria from T cells and macrophages.^45,76

The mitochondrial level shift promotes the proliferation of cancer cells and the immune escape of tumor cells. A possible mechanism is that tumor cells acquire mitochondria in the immune microenvironment and have enhanced glucose uptake after metabolic reprogramming, which competes with tumor-infiltrating lymphocytes (TILs) for glucose and biosynthetic precursors. This competition results in the aberrant metabolic function of TILs and stimulation of immunosuppressive pathways such as PD1, which ultimately leads to T-cell depletion and cancer progression.^77,78

Targeting Mitochondria in Cancer Therapy

The discovery of meaningful mitochondria-associated tumor markers and targeting of mitochondria in cancer cells and the immune microenvironment may provide an alternative approach to cancer treatment.⁷⁹ In recent years, researchers have conducted extensive studies on mitochondria as a cancer treatment strategy. The research has mainly focused on mitochondrial metabolism, structural abnormalities, and protein drugs (Table 1).

Mitochondrial Metabolic Reprogramming-Related Tumor Markers

Gene regulation precisely regulates cellular metabolism to maintain cellular homeostasis and normal function, and dysfunctional cellular metabolism has become a key determinant of tumor pathology.⁸⁰ Mitochondria play a central role in lipid metabolism, and mitochondrial activity depends on lipid exchange between the inner mitochondrial membrane (IMM) and the outer mitochondrial membrane (OMM).^81,82 Abnormalities in mitochondrial lipid metabolism have been demonstrated in both solid and hematologic tumors.^83,84 Abnormalities in mitochondrial lipid metabolism are closely related to mitochondrial metabolic reprogramming, and many cancer cells rely on ab initio fatty acid synthesis (FAS) for proliferation.^85,86

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in cancer cells that undergo metabolic reprogramming. In normal tissue cells, HIF-1 expression is low, while in tumor cells, it is significantly increased.⁸⁷ Under hypoxia in the microenvironment of tumor tissues, HIF-1 expression increases, which in turn regulates various vital substances in the glycolytic pathway of tumor cells, such as glucose transporter proteins (GLUT1 and GLUT3), hexokinase-1, hexokinase-2, enolase-1, phosphoglycerate kinase-1, pyruvate kinase-M2, and lactate dehydrogenase. Elevated expression of pyruvate kinase-M2 promotes tumor cell proliferation and angiogenesis, while abnormalities in glucose transport proteins promote tumor metastasis.^88,89 WZB117 is an extensively studied small molecule inhibitor of GLUT1, and has been found to improve anti-drug efficacy in combination with anti-tumor drugs in breast and endometrial cancers.^90,91 2-Deoxy glucose (2-DG) can sensitize chemotherapeutic agents by regulating glycolysis, intracellular ROS production and endoplasmic reticulum stress.⁹² This effect has been demonstrated in clinical glioblastoma and breast cancer patients.⁹³ Similar results have been obtained in vivo in non-small cell lung cancer and osteosarcoma models.⁹⁴ 3-Bromopyruvate acid (3-BrPA), and oxamate (OXM) have shown good efficacy in clinical or animal model studies of brain tumors.^95,96

However, some scholars believe that the metabolic reprogramming of tumor cells is complex and that metabolic reprogramming enables tumor cells to have bi-directional metabolism, supplying energy through both glycolysis and oxidative phosphorylation, i.e., the “reverse-Warburg” pathway.^97,98 When glucose is overconsumed and undersupplied, lactic acid buildup leads to lactic acidosis, and the glycolytic pathway is inhibited, exhibiting a form of energy supply dominated by oxidative phosphorylation.^99,100 This suggests that crucial enzymes or metabolites in the tricarboxylic acid cycle can also serve as mitochondrial metabolic reprogramming-related tumor markers. In low-grade gliomas, heterozygous mutations in isocitrate dehydrogenase (IDH) 1/2 not only result in a reduced ability of IDH to bind isocitrate but also promote the conversion of α-ketoglutarate to D-2-hydroxyglutarate, which further promotes the invasive growth of glioblastomas.¹⁰¹ Yuan et al¹⁰² found significant downregulation of succinate dehydrogenase A and B subunits in a mouse HCC model, which allowed succinate accumulation and ultimately promoted the proliferation of hepatocellular carcinoma cells.

In addition, tumor cells undergoing aerobic glycolysis accumulate abundant glycolytic intermediates. These intermediates are involved in nucleotides, non-essential amino acids, and fatty acids from scratch.¹⁰³ In addition to the involvement of glycolytic intermediates in its metabolism, oncogenic alterations in cancer cells reprogram the metabolism of glutamine in mitochondria, providing an essential source of carbon and nitrogen for the growth and proliferation of cancer cells through enhanced glutamine catabolism. This results in significantly lower levels of glutamine in the blood of patients with tumors than in normal subjects, as seen in triple-negative breast cancer. Elevated glutaminase expression leads to increased glutamine metabolism, causing its levels in the blood to decrease.^104,105 Under hypoxia, HIF-2α mediates overexpression of SLC1A5, an N-terminal targeting signal used for mitochondrial localization. Overexpression of SLC1A5 results in increased glutamine-induced ATP production and glutathione synthesis, which endows pancreatic cancer cells with gemcitabine resistance and protects against tumor cell growth and invasion.¹⁰⁶

Metabolic alterations in the mitochondria provide energy for tumor growth and proliferation, and targeting and regulating this metabolism may be an effective strategy for cancer therapy. Xu et al¹⁰⁷ developed a platform using mitochondria-targeted RNA nanoparticles for breast cancer, which specifically translocated siRNA into mitochondria to down-regulate the expression of mtDNA-encoded proteins in order to enhance the production of ROS, induce mitochondrial damage, and effectively regulate mitochondrial metabolism. Targeting the tricarboxylic acid cycle, such as by inhibiting mutant isocitrate dehydrogenase by AGI-5198, reduces the formation of 2-hydroxyglutarate and induces differentiation of glioma cells.¹⁰⁸

Tumor Markers Associated with Mitochondrial Structural Abnormalities

Abnormalities in the mitochondrial structure have been associated with the development of a variety of tumors.

Under normal conditions, the mitochondrial membrane is selective for substances, ions, and small molecules that do not easily pass through the inner mitochondrial membrane. This selectivity ensures the stability of mitochondrial function.⁵⁷ When the mitochondrial outer membrane protein Bcl-2 interacts with the pro-apoptotic proteins Bax and Bak, it can change the permeability of the mitochondrial membrane. When hepatocytes become cancerous, Bax and Bak form a differential distribution in hepatocellular carcinoma cells and mitochondria. This differential distribution is the same as that produced by low expression of apoptotic proteins, which both block their apoptosis and promote their growth and proliferation.^109,110 Adenine Nucleotide Translocator 2 is associated with cell growth. It is specifically expressed in the inner mitochondrial membrane of proliferating tissues and tumor cells. It inhibits mitochondrial membrane permeability and promotes anti-apoptotic properties and drug resistance.¹¹¹

The maintenance of mitochondrial kinetic homeostasis is essential for the maintenance of normal cellular function in the body.^112,113 Mitochondrial dynamics mainly include the movement of mitochondria along the cytoskeleton, regulation of mitochondrial structure, and interconnections mediated by fusion or division processes.^114-116 The phenomenon of mitochondrial fusion occurs depending on the different states of the cell, and the key role is to facilitate communication between mitochondria and the host cell.¹¹⁷ When cellular oxygen demand increases for various life activities, mitochondrial fusion promotes OXPHOS, increases ATP production, and balances the distribution of mtDNA between damaged and healthy mitochondria to maximize the maintenance of normal cellular life activities.¹¹⁸ For the organism, mitochondrial fusion is not completely harmless. Clement¹¹⁹ et al found that the development of acute myeloid leukemia (AML) is dependent on mitochondrial fusion. MYLS22, a small compound optic atrophy 1 (OPA1) inhibitor, has an antitumor effect by targeting mitochondrial fusion and disrupting mitochondrial respiration and reactive oxygen species (ROS) production, resulting in a cell cycle arrest at the G0/G1 transition. Mitochondrial fission often precedes mitochondrial fission and autophagy, and fission promotes mitochondrial quality control by eliminating damaged or dysfunctional mitochondria and facilitates the process of apoptosis in abnormal cells.^120,121 Brocket¹²² et al found that mitochondrial fission causes a decrease in breast cancer-related gene expression Akt and ERK signaling. l-alpha-Lysophosphatidylethanolamine (LEP) promotes mitochondrial fission and controls disease progression and metastasis in patients with triple-negative breast cancer. Each step of mitochondrial dynamics is precisely regulated by upstream cascade signals such as AMPK, JNK, Pgc1-α, Pgc1-β, ROS, ca²⁺, and RAS.¹²³

Kinetic imbalance can favor cancer development.¹²⁴ A decrease in mitochondrial fusion protein 1 or an increase in dynamin-associated protein 1 can be found in hepatocellular carcinoma,¹²⁵ gastric carcinoma,¹²⁶ prostate cancer,¹²⁷ and breast cancer brain metastasis tissues,¹²⁸ which synergistically leads to enhanced mitochondrial fragmentation and promotes tumor progression. A protein called OPA1, localized in the inner mitochondrial membrane and membrane space, is reportedly involved in mitochondrial fusion and its oligomerization at cristae junctions, and oligomeric interactions can further regulate mitochondrial cristae structure.^129,130 The expression of this protein increases expression in ovarian cancer, which reduces mitochondrial cristae connectivity and promotes anti-apoptotic effects in tumor cells.^131,132

mtDNA variants are prevalent in malignant tumors, mainly including mtDNA mutations, increased or decreased copy number of mtDNA, etc., and such variants do not exist in normal tissue cells.¹³³ This may be because cancer cells are mainly energized by aerobic metabolism and glycolysis, both of which cause mitochondrial DNA (mtDNA) damage via ROS and mtROS. The imperfect repair system for mtDNA damage and the lack of protection by histones make it more susceptible to mutations.^134-136 Mutations occur with altered mitochondrial energy metabolism that can drive cellular transformation and tumorigenic processes, promote tumor cell proliferation and adaptation to new environments, and contribute to tumor aggressiveness and drug resistance.¹³⁷ mtDNA mutations can be found in thyroid cancer, neurofibromatosis, hepatocellular carcinoma, breast cancer, small-cell lung cancer, colorectal cancer, and nasopharyngeal carcinoma.^138-141 As reported in a few studies, no meaningful mtDNA copy number changes were found between the blood of patients with metastatic breast cancer and normal controls; this suggests that mitochondria from tumor tissues can enter the blood circulation. In vitro experiments showed that ONC201 induced mitochondrial fission in the MB231 line of triple negative breast cancer cells and ultimately targeted pre-mitochondrial DNA to promote their death.¹⁴² Therefore, mtDNA is expected to be a potential marker for the diagnosis of malignant tumors.¹⁴³

A normal mitochondrial structure and proteins are essential for maintaining normal mitochondrial function. In human acute myeloid leukemia, enhanced BCL-2 expression leads to inhibition of mitochondria-mediated apoptosis and is associated with the development of resistance to BCL-2 inhibitors.^144,145 In contrast, targeting the mitochondrial protein CLPB with therapy leads to structural and functional defects in the mitochondria, thereby sensitizing AML cells to apoptosis and alleviating BCL-2 inhibitor resistance in acute myeloid leukemia.¹⁴⁵ In hepatocellular carcinoma, mitochondrial translocation proteins are highly expressed, leading to accumulation of P62 and interfering with autophagy, preventing Nrf2 from undergoing proteasomal degradation, inhibiting tumor apoptosis, and upregulating PD-L1 to aid in immune escape.¹⁴⁶ Targeting mitochondrial proteins suggests new ideas for cancer treatment.

Mitochondrial Quality Control-Related Tumor Markers

Mitochondria contain more than 1000 proteins that regulate mitochondrial function. Mitochondria have developed multiple levels of protein quality control to ensure organelle homeostasis, and based on the severity of mitochondrial dysfunction, specific quality control mechanisms are activated.¹⁴⁷ Together with the chaperone proteins of the HSP10, HSP60, and HSP70 families, mitochondrial proteases provide important quality control and the first line of defense against mitochondrial damage mediated by the accumulation of unfolded or damaged proteins and unassembled subunits of large mitochondrial complexes.¹⁴⁸ Malignant tumor development is promoted when mitochondrial mass-regulatory mechanisms are dysregulated.¹⁴⁹ LONP1 upregulation has been reported in non-small cell lung cancer and colorectal cancer, which plays a role in mitochondrial metabolic reprogramming and promotes tumor growth. Mitochondrial dysfunction in cancer persists, keeping the mitochondria in a state of chronic stress, allowing for increased mtROS production, accumulation of mitochondrial DNA mutations, and worsening of the mitochondrial dysfunction cycle.¹⁵⁰ This stress accumulation triggers the transactivated mitochondrial unfolded protein response (UPRMT), which relieves mitochondrial stress in tumor cells by removing mitochondrial proteins that have been damaged by mtROS as well as by facilitating protein folding or assisting the cancer cells in promoting tumor growth and proliferation.¹⁵¹ In addition, mitochondrial autophagy, an essential quality control mechanism within the cell, regulates the stability of the intracellular environment by removing damaged mitochondria and avoiding the accumulation of dysfunctional mitochondria, thereby negatively influencing cancer progression and enhancing its response to therapy.¹⁵² However, Humpton,¹⁵³ Sowter¹⁵⁴ et al found that mitochondrial autophagy mediated by different mechanisms does not always play an oncostatic role in different cancer types. Therefore, targeting mitochondrial quality control and autophagy-related proteins in different cancers is likely to be a new approach to cancer treatment.

Table 1.

Anti-Tumor Drugs Targeting Mitochondria.

Target Category	Drug Category	Drug Name	Target
Mitochondrial metabolism	Glycolysis inhibitor	WZB117	GLUT
	Glycolysis pathway enzyme inhibitors	2-DG	HK
		3-BrPA	LDH
		OXM	LDH
	Downregulation of mtDNA-encoded protein expression	mitochondria-targeted RNA nanoparticles	Increased generation of ROS
	Oxidative phosphorylation inhibitor	AGI-5198	NAD⁺
Mitochondrial dynamics	-	ONC201	mtDNA
	mitochondrial fusion	MYLS22	OPA1
	mitochondrial fission	LEP	-

Footnotes: GLUT: Glucose transporter protein. 2-DG: 2-Deoxy glucose. HK: Hexokinase. 3-BrPA: 3-Bromopyruvic acid. LDH: Lactate dehydrogenase. OXM: oxamate. NAD⁺: Nicotinamide adenine dinucleotide. mtDNA: mitochondrial DNA.

Conclusion

This review comprehensively describes the role of mitochondrial abnormalities in cancer from various aspects of mitochondrial energy metabolism, structural alterations, kinetic changes and quality control. Mitochondria are powerful and complex, even though the link between mitochondria and malignancy has been extensively studied, questions regarding how mitochondria affect specific tumor types, the interaction of mitochondrial dysfunction with the tumor microenvironment, and the specific regulatory mechanisms of mitochondrial metabolic reprogramming remain unclear. Nevertheless, our review also provides strategies and approaches for clinically targeting mitochondrial antitumor therapy. Future research should focus on developing novel diagnostic tools based on mitochondrial biomarkers, exploring therapeutic strategies that target mitochondrial function, and combining multidisciplinary research to gain a deeper understanding of the relationship between mitochondria and tumor development, with the aim of providing new ideas and methods for early diagnosis and individualized treatment of tumors. These efforts will help to improve the efficiency of tumor treatment and reduce the burden on patients and society.

Footnotes

Author Contributions

Q-XL, Z-RL and WZ: Conceptualization; Z-RL and WZ: Writing-original draft; Q-XL: Funding acquisition; S-WG & G-YQ: review; JG: project administration; JZ: supervision; J-DH & LK: editing.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by the Precision Medicine Joint Cultivation Program of the Natural Science Foundation of Hebei Province (No. H2022307024).

Ethical Statement

ORCID iDs

Zhiru Li

Wu Zhang

Shaowei Guo

Guoyan Qi

Jiandi Huang

Qingxia Li

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

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A Review of Advances in Mitochondrial Research in Cancer

Abstract

Background

Purpose

Conclusions

Keywords

Introduction

Relationship Between Mitochondria and Cancer

Mitochondrial and Energy Metabolism Reprogramming in Cancer Cells

Effect of Mitochondria on Tumor Cell Viability

Mitochondrial Dysfunction and Oxidative Stress

Mitochondria in the Tumor Microenvironment

Mitochondrial Transfer and Cancer Proliferation

Targeting Mitochondria in Cancer Therapy

Mitochondrial Metabolic Reprogramming-Related Tumor Markers

Tumor Markers Associated with Mitochondrial Structural Abnormalities

Mitochondrial Quality Control-Related Tumor Markers

Conclusion

Footnotes

Author Contributions

Declaration of Conflicting Interests

Funding

Ethical Statement

ORCID iDs

Data Availability Statement

References