Mitochondrial DNA-targeted therapy: A novel approach to combat cancer

Abstract

Mitochondrial DNA (mtDNA) encodes proteins and RNAs that are essential for mitochondrial function and cellular homeostasis, and participates in important processes of cellular bioenergetics and metabolism. Alterations in mtDNA are associated with various diseases, especially cancers, and are considered as biomarkers for some types of tumors. Moreover, mtDNA alterations have been found to affect the proliferation, progression and metastasis of cancer cells, as well as their interactions with the immune system and the tumor microenvironment (TME). The important role of mtDNA in cancer development makes it a significant target for cancer treatment. In recent years, many novel therapeutic methods targeting mtDNA have emerged. In this study, we first discussed how cancerogenesis is triggered by mtDNA mutations, including alterations in gene copy number, aberrant gene expression and epigenetic modifications. Then, we described in detail the mechanisms underlying the interactions between mtDNA and the extramitochondrial environment, which are crucial for understanding the efficacy and safety of mtDNA-targeted therapy. Next, we provided a comprehensive overview of the recent progress in cancer therapy strategies that target mtDNA. We classified them into two categories based on their mechanisms of action: indirect and direct targeting strategies. Indirect targeting strategies aimed to induce mtDNA damage and dysfunction by modulating pathways that are involved in mtDNA stability and integrity, while direct targeting strategies utilized molecules that can selectively bind to or cleave mtDNA to achieve the therapeutic efficacy. This study highlights the importance of mtDNA-targeted therapy in cancer treatment, and will provide insights for future research and development of targeted drugs and therapeutic strategies.

Keywords: Cancer; Cancer therapy; Mitochondria; mtDNA.

Graphical abstract

Fig. 1

The detailed structure of mtDNA. The whole mtDNA sequence included a total of 37 coding genes and a D-loop region. And the coding genes including 13 essential proteins (ND1, ND2, ND3, ND4, ND4L, ND5, ND6, CYTB, COX1, COX2, COX3, ATP6 and ATP8), 22 tRNAs (TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL1, TL2, TK, TM, TF, TP, TS1, TS2, TT, TW, TY and TV) and 2 rRNAs (12s rRNA and 16s rRNA).

Fig. 2

Schematic diagram of four typical modes of intercellular mtDNA transfer. Stimulation of TME tissues by endogenous factors, such as damaged mtDNA in tumor cells, or exogenous factors like oxidative stress, inflammatory response and pathological stimuli can trigger intercellular transfer of mtDNA. mtDNA transfer mainly includes four typical forms: tunneling nanotubes (TNTs), cell fusion, gap junction channels (GJCs) and extracellular vesicles (EVs). Multiple mechanisms frequently co-exist and synergistically interact in TME.

Fig. 3

The main aspects of indirect targeted therapy. We summarize the related studies of indirect targeted therapy into three categories, including increasing ROS, influencing genetic functions of mtDNA and activating immunity. Treatments that disrupt the normal states of these aspects will further cause damage of mtDNA, resulting in tumor suppression mediated by mitochondrial dysfunction. BER, base excision repair; IFN, interferon; IL-6, interleukin- 6; mtRNAP, mitochondrial RNA polymerase; TBK1, TANK Binding Kinase 1; TFAM, mitochondrial transcription factor A; TFB2M, mitochondrial transcription factor B2; TGF-β, transforming growth factor beta.

Fig. 4

Assembly of transcription initiation complexes. TFAM and three other components (TFB2M, mtRNAP and promoter DNA) form a complex on the mtDNA to start the expression process. At the beginning of the transcription, TFAM firstly binds to DNA 16–39 nt upstream of the transcription start site and induces a ∼180° bend into DNA (Hillen et al., 2017; Rubio-Cosials et al., 2011). And then the helix D in the N-terminal extension of mtRNAP will link with the HMG Box B domain of TFAM, resulting in anchoring to the promoter (Hillen et al., 2017). The formed pre-IC lacks DNA specificity and transcriptional activity, unless the N-terminus of TFB2M bound to the active site of mtRNAP and induces conformational changes in mtRNAP (Morozov et al., 2015). mtRNAP, mitochondrial RNA polymerase; TFAM, mitochondrial transcription factor A; TFB2M, mitochondrial transcription factor B2.

Fig. 5

The main aspects of direct targeted therapy. We summarize the relevant research into three aspects: carrier systems, metal complexes and application of phototherapy. And among the studies we included, carrier systems, metal complexes, and phototherapy frequently overlapped in their research techniques, drug construction, therapeutic effects and so on. We suspect that future research may need to enhance the integration of the three methods to develop more effective strategies. DLC, delocalized lipophilic cation; PCT, photochemotherapy; PDT, photodynamic therapy; PTT, photothermal therapy; TPP, triphenylphosphonium.