Professor Feng Du's team at the School of Basic Medical Sciences, Guangzhou Medical University, has uncovered a new mechanism for mitochondrial DNA (mtDNA) quality control. They reported that mitochondrial transcription factor A (TFAM) acts as a receptor for autophagy to mediate the clearance of cytoplasmic mtDNA, thereby limiting inflammatory responses. The related findings were published online on May 23rd in Nature Cell Biology.
TFAM mediates the autophagic clearance of mtDNA under stress conditions, thereby inhibiting the activation of the cGAS-STING pathway. Research team provided the figure.
In stress conditions, TFAM is released into the cytoplasm along with mtDNA. TFAM interacts with the autophagy key protein LC3 to mediate the lysosomal-dependent clearance of mtDNA and TFAM. Disruption of the TFAM-LC3B interaction leads to further accumulation of mtDNA under stress conditions, exacerbating the activation of the cGAS-STING inflammatory pathway.
Mitochondria are crucial organelles for cellular homeostasis and energy production. Various stresses can cause mitochondrial dysfunction, leading to the release of mtDNA into the cytoplasm, activating inflammatory pathways and contributing to the onset of various diseases. Accumulation of mtDNA in the cytoplasm can sustain inflammation and cellular dysfunction, exacerbating disease progression. Therefore, elucidating the clearance process is essential.
In previous studies, the Feng-Du team found that the mitochondrial inner membrane protein PHB1 regulates the detachment-aggregation of the mitochondrial membrane permeability transition pore, controlling the mechanism of mtDNA release from the mitochondrial membrane. Building on this research, the team further explored the release of mtDNA and its binding protein TFAM into the cytoplasm during oxidative stress or inflammatory responses. TFAM interacts with the autophagy protein LC3B, acting as an autophagic receptor to mediate the clearance of mislocalized cytoplasmic mtDNA, inhibiting the cGAS-STING pathway to alleviate mtDNA-induced inflammatory responses.
This study uncovered a DNA enzyme-independent pathway for mtDNA degradation, revealing a new mechanism for mtDNA quality control. It holds broad significance for understanding various pathologic states related to immune imbalance and may offer potential therapeutic approaches for inflammation triggered by mtDNA imbalance.
For more information, refer to the related paper: https://doi.org/10.1038/s41556-024-01419-6
