Mitochondrial G-quadruplex (mt-G4)

Mitochondrial G-quadruplexes (mt-G4s) are non-canonical, four-stranded secondary structures formed by guanine-rich sequences within the mitochondrial genome (mtDNA). These structures are predominantly located in regulatory regions like the displacement loop (D-loop) and within coding sequences for essential respiratory subunits, such as ND2 and ND5 [1][2]. Biologically, mt-G4s serve as critical regulators of mitochondrial homeostasis, influencing the initiation and progression of mtDNA replication and transcription by acting as physical barriers to mitochondrial RNA polymerase (POLRMT) and DNA polymerase gamma (POLG) [3][4]. In the context of pathology, mt-G4s are increasingly recognized as viable therapeutic targets in oncology, as their stabilization can trigger mitochondrial dysfunction, oxidative stress, and subsequent apoptosis in cancer cells [5]. Small molecule ligands, including pyridostatin and mitochondria-targeted derivatives like Mito-PDS, have been developed to bind and stabilize these structures, effectively reducing mtDNA copy numbers and impairing cellular bioenergetics [1][6]. Despite their potential, a primary challenge in targeting mt-G4s is achieving sufficient selectivity to avoid off-target effects on nuclear G-quadruplexes, which could lead to systemic toxicity [2]. Citations: [1] Falabella, M., et al. (2019) Nucleic Acids Res; [2] Dong, S., et al. (2022) Front Oncol; [3] Besnard, C., et al. (2021) Int J Mol Sci; [4] Lyu, J., et al. (2021) FEBS Lett; [5] Huang, W. C., et al. (2015) Sci Rep; [6] Wang, Z. F., et al. (2020) Chem Commun.

Other names

Mitochondrial DNA G-quadruplexmtDNA G-quadruplexMitochondrial G4 DNAmt-G4 DNA

Stabilization of G-quadruplex structures to inhibit mitochondrial DNA replication and transcription, leading to mitochondrial dysfunction and apoptosis.