Authors
Ge, B., Wang, L., Peng, C., Chen, Q., Huang, J., Bu, W., Wu, X., Duan, Y., Liu, S., Cheng, H., Ma, M., Cheng, Y., Wang, J., Yang, H., Zheng, R., Wang, J., Huang, X.
Abstract
Innate immune memory typically emphasizes nuclear chromatin remodeling that determines transcriptional memory in monocytes and macrophages. Here, we show that compaction of mitochondrial DNA (mtDNA), governed by mitochondrial transcription factor A (TFAM) abundance and mtATP-dependent remodeling, defines the transcriptional and functional state of trained macrophages. While typical pathogen-associated molecular pattern (PAMPs) triggered mtDNA accessibility, Bacillus Calmette-Guerin (BCG) effector PE18 directly interacted with and activated SLC25A5 to reduce mtATP levels, thereby inhibiting TFAM degradation by AFG3L2. Accumulated TFAM restricts mtDNA accessibility, suppressing the transcription of the mtNd1 and thereby reducing mtNd1-mediated mtROS production, which diminishes the trained capacity of macrophages against secondary infections. Notably, BCG{Delta}pe18 maintains macrophage's cytokine transcriptional capacity independent of classical nuclear histone modifications. Moreover, BCG{Delta}pe18 provides robust and lifelong protective immunity against Mycobacterium tuberculosis (Mtb) infection. These findings reveal mitochondrial genome as a regulatory entity in trained immunity, and suggest a potential strategy for improving vaccine performance.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 12 Nov 2025.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 39
- Comments 0