Introduction

The incidence of breast cancer has gradually increased at a rate of 0.5% per year since 2000 [1]. However, with a better understanding of cancer and the popularization of early breast cancer screening, such as mammography, breast color ultrasound and breast magnetic resonance screening, the mortality rate of breast cancer has decreased slightly in recent years. Early menarche, late menopause, family history, and old age are all high-risk factors for breast cancer [2]. Moreover, the occurrence of breast cancer is related to mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/2). Breast cancer is a heterogeneous disease involving genetic and environmental factors. As one of the malignant tumors with the highest mortality rates among women in the world, due to the heterogeneity and complexity of breast cancer, it is often difficult for a single treatment method to achieve the desired effect. Patients with early- and middle-stage breast cancer are mainly treated with surgery, and adjuvant treatment after surgery can reduce the risk of recurrence. Although the survival rate of patients with advanced breast cancer is very low, with the application of new targeted drugs, the survival period can be extended to 2–3 years [3]. Therefore, further study of clinical treatment methods for breast cancer is urgently needed.

In recent years, our understanding of mitochondria and mitochondrial dynamics has increased significantly; mitochondria not only provide energy to cells but also participate in important pathways, such as lipid metabolism, oxidative stress, cell differentiation, cell transmission, and apoptosis. An increasing number of studies have confirmed that mitochondria play an indelible role in cancer progression. Here, we describe the close relationship between mitochondrial dynamics and breast cancer progression, as well as the potential of targeting mitochondria in the treatment of breast cancer.

Mitochondria and mitochondrial dynamics

Mitochondria are double-membrane organelles that are involved mainly in oxidative phosphorylation (OXPHOS). The mitochondrial membrane comprises the outer mitochondrial membrane (OMM), the inner mitochondrial membrane (IMM), the mitochondrial membrane gap, and the mitochondrial matrix. It is the site of oxidative metabolism in eukaryotes and the main site of aerobic respiration in cells. It can synthesize ATP through oxidative phosphorylation [4] and can also promote intracellular Ca2+balance [5]. Mitochondria are also the main place where reactive oxygen species (ROS) are produced. It is mainly produced by complex i and complex II in the oxidative respiratory chain. ROS refers to the general term for oxygen-containing free radicals and peroxides that are easy to form free radicals related to oxygen metabolism in the organism. ROS can directly act on cytochrome C on the lipid membrane to release it, causing cell damage. ROS can also damage cell DNA and promote the formation of cancer cells (Fig. 1). In addition, mitochondria are involved in cell apoptosis and induce autophagy. In brief, mitochondria are essential for maintaining cellular homeostasis.

Fig. 1
figure 1

ROS is generally produced in complex I and complex II of the oxidized respiratory chain. It can release cytochrome C on the lipid membrane, causing cell damage. ROS can also directly damage cell DNA and promote tumor formation. a. IMM: Inner mitochondrial membrane; b. NADH: Nicotinamide adenine dinucleotide; c. FADH2: Flavine adenine dinucleotide; d. Cty-C: Cytochrome C; e. ROS: Reactive oxygen species

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Mitochondrial dynamics refers to the dynamic balance between mitochondrial division and fusion. Most of the enzymes required are GTP enzymes, such as DRP1, MFN1/2, and OPA1, which are members of the Dynamin family [6] (Fig. 2). Mitochondrial dynamics are essential for maintaining the stability of mitochondrial function and not only affect the cell cycle during mitosis but also affect cell death [7, 8]. Studies have shown that mitochondrial dynamics play a key role in many diseases, such as degenerative diseases of the nervous system, cancer, diabetes, and cardiovascular ischaemia‒reperfusion injury [9].

Fig. 2
figure 2

Schematic diagram of mitochondrial dynamics. a. Drp 1: dynamin-related protein-1; b. Mfn 1: Mitofusin 1; c. Mfn 2: Mitofusin 2; d. Fis 1: Fission, Mitochondrial 1; e. Mff: mitochondrial fission factor; f. Mid49: mitochondrial dynamics proteins of 49 kDa; g. Mid51: mitochondrial dynamics proteins of 51 kDa; h. IMM: inner mitochondrial membrane

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Mitochondrial fission refers to the process by which a mitochondrion divides into two mitochondria through multiple steps to adapt to cell survival. The motility protein required for mitochondrial fission is the GTP enzyme DRP1, which can be activated by the phosphorylation of the MAP kinases ERK1 and ERK2. Tong Xu et al. reported that when Porphyromonas gingivalis (Pg) infected endothelial cells and caused mitochondrial fragmentation, the phosphorylation of DRP1 at Ser616 significantly increased [10]. When mitochondria begin to undergo fission, DRP1 is recruited from the cytoplasm to the outer mitochondrial membrane and binds to the receptors Fis1, Mff, Mid49, and Mid51 to shrink the intima and outer membrane, thereby mediating the division of mitochondria [11,12,13]. In addition, Elena Smirnova reported that the inhibition of mitochondrial fission caused by DRP1 mutations can lead to the excessive fusion of tubular small bodies of mitochondria [14].

The order of mitochondrial fusion is generally outer membrane fusion first and then inner membrane fusion. During the fusion process, substances in mitochondria, such as mtDNA, proteins and metabolic substances, are exchanged. Three large GTP enzymes are needed: the outer membrane proteins MFN1 and MFN2 and the intimal protein OPA1 [15, 16]. MFN1 and MFN2 maintain their stability through the regulation of proteolytic ubiquitination [17]. The formation of the crest after mitochondrial fusion is usually related to the OPA1 protein [18]. Under normal circumstances, the fusion of the outer membrane and the inner membrane is balanced, but due to genetic mutations, the fusion of the inner membrane and the outer membrane can also occur independently of each other.

The role of mitochondrial dynamics in cancer

Mitochondrial dynamics may be related to cancer epithelial mesenchymal transformation, invasion, and metastasis [19]. An imbalance in mitochondrial dynamics, that is, an imbalance in fission and fusion, is an important factor leading to cancer progression [20,21,22,23]. In addition, Poorva Ghosh reported that increased mitochondrial fusion can promote oxidative phosphorylation and that increased fission can promote glycolysis [24].

Metastasis is an important cause of cancer death [25]. Compared with that of normal cells, the microenvironment of cancer cells generally presents a state of hypoxia in which there are many reactive oxygen species (ROS) [26]. Moreover, high levels of ROS promote mutations in mitochondrial DNA (mtDNA), changing mitochondrial function [27], and we also found that there are more fragmented mitochondria in metastatic cancer tissues; often, these cells have high DRP1 expression, while MFN is expressed at low levels. High DRP1 expression or low MFN expression results in mitochondrial fragmentation and enhances cancer metastasis [28]. In contrast, low DRP1 expression or high MFN expression causes mitochondria to become clustered or rod-shaped, thereby inhibiting the metastasis of cancer cells. Jalees Rehman discovered that inhibiting the fission of mitochondria prevents the metastasis of lung cancer cells (Table 1) [29].

Table 1 The role of fission and fusion-related GTP enzymes on cancer progression
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Mitochondrial dynamics are closely related to the development of breast cancer

In recent years, increasing research has confirmed the important role of mitochondrial dynamics in the progression of breast cancer. By targeting Drp1 to inhibit mitochondrial fission, brain metastasis of breast cancer was alleviated [40]. In MDA-MB-231 cells treated with silymarin, the expression of MFN1/2 increased significantly, and the expression of DRP1 decreased, thereby promoting mitochondrial fusion and inhibiting the migration of breast cancer cells [41]. Estrogen is one of the important factors that cause breast cancer [42], Jorge Sastre-Serra et al. analyzed 17ß-oestradiol-treated MCF-7 cells by RT‒PCR and found that the expression of fusion mRNAs (Mfn1/2 and Opa1) increased and that of fission-related genes (Drp1 and Fis1) decreased, they unbalance mitochondrial fission and fusion, causing mitochondrial function to decrease [43]. IKK, an important member of the NF-kB pathway, has been extensively studied in recent years. It has been confirmed that it acts as a carcinogen and is related to the progression of a variety of cancers. Ruoyan Xu et al. reported that IKK2 inhibits the use of pyruvate in the tricarboxylic acid cycle in mitochondria in breast cancer cells, thereby causing mitochondrial dysfunction, inhibiting OXPHOS, and promoting the progression of breast cancer [44]. Phosphatidylserine decarboxylase (PISD) has been shown to promote mitochondrial fission [45]. With the exogenous addition of PISD to MDA-MB-231 cells, we found that the mitochondrial membrane potential changed and inhibited the growth of breast tumor cells (Table 2) [46].

Table 2 Regulation of the progress of breast cancer by fusion and fission factors
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Mitochondrial fission and breast cancer

Several studies have shown that by regulating the expression of mitochondrial fission factors, the proliferation and invasion of breast cancer cells can be suppressed to achieve therapeutic effects [48]. Moreover, highly expressed mitochondrial fission factors can also be used as prognostic indicators. By analyzing metastatic and invasive breast cancer cells, we found that the expression of DRP1 was greater in the former, which suggested that the upregulation of DRP1 expression may be an early signal of breast cancer metastasis [48].

One of the most critical steps in breast cancer progression before metastasis is the formation of lamellipodia at the leading edge of the cell [49]. The formation of these lamellipodia depends on actin and requires a large amount of ATP. The formation of lamellipodia at the leading edge of a cell refers to the formation of a sheet-like structure in the leading edge area to help cells move and invade tissue. The formation of this structure is essential for the metastasis of breast cancer cells because it can help them pass through the blood vessel wall or tissue gaps and enter blood vessels or lymphatic vessels, thereby facilitating metastasis to distant organs [50, 51] (Fig. 3). In in vitro experiments, we first used targeted siRNA transfection technology to reduce the expression of Drp1 in MDA-MB-231 breast cancer cells by 85%. Then we found that the diffusion rate of MDA-MB-231 cells with low or no expression of DRP1 protein was significantly reduced, and the percentage of plate-shaped pseudopods was reduced by about 60%. In contrast, cells with low Mfn1 protein expression exhibited accelerated diffusion and lamellipodium formation [48].

Fig. 3
figure 3

Related signaling pathways involved in the mitochondria of breast cancer. a. PEP: phosphoenolpyruvate; b. PYR: pyruvate; c. Drp 1: dynamin-related protein-1; d. Mfn 2: Mitofusin 2; e.PKM2: Pyruvate kinase isozyme type M2; f. NICD1: Notch intracellular domain 1

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Mitochondrial fission regulator 1 (MTFR1) is a gene encoding a mitochondrial protein, and studies have shown that the abnormal expression of the MTFR1 protein is closely related to the occurrence and development of diseases such as tumors, neurodegenerative diseases, and metabolic diseases. By analyzing the tumor profile in a TCGA cohort, we found that MTFR1 is highly expressed in Her2-positive or ER-negative breast cancer and is associated with poor prognosis [52]. Moreover, we also found that high MTFR1 expression is negatively correlated with DNA methylation and that low MTFR1 methylation is often related to the occurrence of cancer [52]; however, the underlying mechanism is unclear. Guanming Lu also reported that mitochondrial fission regulator 2 (MTFR2) is dependent on HIF1a and HIF2a to transition from oxidative phosphorylation to glycolysis for glucose metabolism. An increase in the expression of this gene is also closely related to tumor progression in breast cancer cells [53].

Studies have proved that the Notch pathway plays an important role in regulating the metastasis of breast cancer stem cells. The expression of Notch1 mRNA is closely related to the poor prognosis of breast cancer [54], and there is a correlation between mitochondria and the Notch pathway. Li Chen et al. found that the activation of NICD1, the main functional region of Notch receptor, promotes the expression of the fission factor Drp1 in mitochondria, thereby promoting the metastasis of breast cancer cells [28] (Fig. 3). Therefore, γ-secretase inhibitors targeting the Notch pathway can be used for clinical treatment [55]. Several studies have shown that mitochondrial fission may affect the development of breast cancer by regulating pathways such as apoptosis and metabolic reprogramming [56]. Apoptosis is an important method of cell death that plays an important role in inhibiting the development of tumors. Abnormalities in mitochondrial fission may lead to abnormal signals in the apoptosis pathway [57], thereby promoting the growth and metastasis of breast cancer cells.

Mitochondrial fusion and breast cancer

The Warburg effect is regarded as an important feature of tumor cell energy metabolism [58]. Normal cells use oxygen to perform OXPHOS in the mitochondria to break down glucose to produce ATP, and cancer cells use glycolysis to breakdown glucose to produce lactic acid and ATP [59]. This effect is regarded as the Warburg effect. Tong Li et al. discovered that PKM2, the M2 subtype of pyruvate kinase, can bind to MFN2, thereby promoting mitochondrial fusion and oxidative phosphorylation and weakening the glycolytic process in cancer cells, thereby inhibiting the proliferation and metastasis of cancer cells [60]. mTOR is an atypical serine/threonine protein kinase and a member of the phosphatidylinositol kinase-related kinase (PIKK) protein family. By regulating the expression and activity of these fusion proteins, mTOR can affect the fusion and division of mitochondria. The mTOR-MFN2-PKM2 pathway mediated by mTOR enhances the interaction between MFN2 and PKM2, which is essential for glycolysis and oxidative phosphorylation in breast cancer cells (Fig. 3). However, high expression of the fusion protein Opa1 is related to poor prognosis in patients with breast cancer. Margherita Zamberlan reported that inhibiting Opa1 can reduce tumor growth, tumor aggressiveness, and neovascularization, thereby inhibiting the metastasis of breast cancer [61].

Mitochondria can be used as new targets for breast cancer treatment

For a long time, the emergence of targeted therapies for breast cancer has brought new hope to breast cancer patients. With the continuous deepening of research, targeted therapy drugs are also constantly being updated and improved (Table 3). Targeted mitochondrial therapy has been regarded as a focus of clinical research [24]. Mitochondrial fission is related to the poor prognosis of breast cancer patients. Therefore, directly or indirectly inhibiting the division of mitochondria inhibits the metastasis of breast cancer [62]. The mitochondrial division inhibitor Mdivi-1, which is a small molecule compound, can bind to DRP1 to inhibit mitochondrial fission, further reducing ATP production and oxidative phosphorylation, thereby promoting the apoptosis of breast cancer cells [63]. In addition, the peptide inhibitor P110 mainly prevents DRP1 from binding to the receptor Fis1, thereby inhibiting mitochondrial fission. Because of its fewer side effects, compared with Mdivi-1, P110 has better prospects in clinical applications.

Table 3 Targeted breast cancer treatment and related signaling pathways
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Promoting mitochondrial fusion can improve the sensitivity of triple-negative breast cancer to chemotherapy. Studies have shown that in mice with MDA-MB231 breast cancer cells, the injection of P-Mito or Mdivi-1 can enhance sensitivity to doxorubicin to the same extent [47]. P-Mito is a polypeptide that can increase mitochondrial fusion and reduce oxidative stress. It has been shown to reduce cancer tissue metastasis and growth in TNBC mice [64].

The poor prognosis of triple-negative breast cancer is related to its high aggressiveness, and some studies have found that the ROS content in triple-negative breast cancer is higher than that in other types of breast cancer, and the strength of tumor aggressiveness is related to the content of ROS [65]. Therefore, eliminating the ROS content in cancer cells may attenuate the metastasis of cancer cells. Peroxide-reducing proteins (Prdxs) in mitochondria have been shown to be upregulated in different types of cancer, especially Prdxs 3 and Prdxs 5. But Prdxs 3 and Prdxs 5 may be associated with drug resistance in cancer. For example, the upregulation of Prdxs 3 in breast cancer is associated with azithromycin resistance [66], and the upregulation of Prdxs 5 in Hodgkin lymphoma is associated with resistance to azithromycin and vincristine [67]. Therefore, targeted therapy of Prdxs is currently a new research direction for cancer treatment, for example, curcumin, an inhibitor of Prdxs 6, has been shown to induce apoptosis of liver cancer cells to treat liver cancer [68]; Ainsliadimer A acts on Prdxs 1 and Prdxs 2 to treat colon cancer and many more [69].

Recent research has shown that mitochondrial transplantation may also become a new option for breast cancer treatment and may prevent a series of toxic side effects caused by traditional radiotherapy and chemotherapy. Jui-Chih Chang used cell-penetrating peptide (Pep-1) to mediate the transport of entire mitochondria to MCF-7 breast cancer cells. Without affecting the function of mitochondria, we found that this approach can reduce not only the biological activity of breast cancer cells [56] but also the occurrence of oxidative stress and drug resistance; however, the execution of this approach is complicated, and thus, this method has not been put into clinical use.

Perspectives and conclusion

In recent years, there has been increasing research on mitochondrial dynamics and cancer progression. In brief, the progression and metastasis of breast cancer are closely related to an imbalance in mitochondrial dynamics. Many experimental studies have shown that in metastatic breast cancer, mitochondrial fusion decreases, fission increases, and mitochondrial fragmentation increases. Further exploration of whether mitochondrial dynamics can truly treat breast cancer and provide targets is critical for clinical treatment. Future research should further clarify the mechanism of action of targeted mitochondrial therapy in the development of breast cancer and identify more effective treatment strategies to improve treatment efficacy in breast cancer patients.