Mitochondria transcription and cancer

Abstract

Mitochondria are major organelles involved in several processes related to energy supply, metabolism, and cell proliferation. The mitochondria function is transcriptionally regulated by mitochondria DNA (mtDNA), which encodes the key proteins in the electron transport chain that is indispensable for oxidative phosphorylation (OXPHOS). Mitochondrial transcriptional abnormalities are closely related to a variety of human diseases, such as cardiovascular diseases, and diabetes. The mitochondria transcription is regulated by the mtDNA, mitochondrial RNA polymerase (POLRMT), two transcription factors (TFAM and TF2BM), one transcription elongation (TEFM), and one known transcription termination factor (mTERFs). Dysregulation of these factors directly leads to altered expression of mtDNA in tumor cells, resulting in cellular metabolic reprogramming and mitochondrial dysfunction. This dysregulation plays a role in modulating tumor progression. Therefore, understanding the role of mitochondrial transcription in cancer can have implications for cancer diagnosis, prognosis, and treatment. Targeting mitochondrial transcription or related pathways may provide potential therapeutic strategies for cancer treatment. Additionally, assessing mitochondrial transcriptional profiles or biomarkers in cancer cells or patient samples may offer diagnostic or prognostic information.

Fig. 1. The structure of mitochondria genome.

The mtDNA is a closed-circular, double-stranded DNA molecule comprising both high-replication and low-replication regions. It encodes 13 mitochondrial respiratory chain proteins, including complexes I (blue), III (red), IV (green), and V (orange), along with 22 tRNAs (brown) and 2 rRNAs (purple) involved in the translation of mitochondrial proteins.

Fig. 2. Structure of mitochondria transcription regulates factors.

The POLRMT structure, visualized through the PDB file (PDBID: 3SPA), exhibits distinct domains: the mitochondrial targeting signal (MTS) in yellow, the N-terminal extension domain (NTE) in orange, the pentatricopeptide repeat domain (PPR) in blue, the N-terminal domain (NTD) in brown, and the C-terminal domain (CTD) in green. The TFAM structure, visualized via the PDB file (PDBID: 4NOD), includes the mitochondrial targeting signal (MTS) in yellow, the High Mobility Group Box A and B domains in blue, and the C-terminal domain (CTD) in orange. The TFB2M structure, visualized by the PDB file (PDBID: 6ERO), includes the mitochondrial targeting signal (MTS) depicted in yellow, the N-terminal rRNA methyltransferase-like domain (NTD) in purple, and the C-terminal domain (CTD) in blue. The TEFM structure, visualized using the PDB file (PDBID: 5OL8), showcases the mitochondrial targeting signal (MTS) in yellow, the N-terminal domain (NTD) in blue, and the C-terminal domain (CTD) in orange. The MTERF structure is represented by the PDB file (PDBID: 3MVA).

Fig. 3. Model of mammalian mitochondrial transcription.

A The initiation complex formed by POLRMT, TFAM and TFB2M assembles in the promoter region. B TFAM and TFB2M disengage from the initiation complex and TEFM binds POLRMT to form the elongation complex. C Transcription from LSP is terminated by MTERF1 that binds the mt-Tl1 sequence.

Fig. 4. Mechanism of mitochondria transcription in cancer progression and the regulation of mitochondria transcription for cancer treatment.

Mitochondrial DNA mutations and inhibition of mitochondrial transcription lead to damage in oxidative phosphorylation, promoting ROS release and modulating signaling pathways such as MAPK/mTOR, AKT, and NF-κB signaling pathways, thereby affecting the proliferation and apoptosis of tumor cells. Silencing of TFAM expression in mitochondria induces metabolic reprogramming in tumor cells, leading to the release of α-KG, which downregulates β-catenin transcriptional activity, suppressing tumor stem cell signaling. Additionally, inhibiting TFAM expression mediates the release of mitochondrial DNA into the cytoplasm, activating the cGAS-STING pathway and promoting autophagy-dependent ferroptosis. Small molecule compounds IMT1 and MtPTAC target POLRMT to inhibit mitochondrial transcription, suppressing mitochondrial OXPHOS and inhibiting tumor cell proliferation.