Loss of Mitochondrial Respiratory Capacity Reshapes Myeloid Cell Function during Mycobacterium tuberculosis infection

Myeloid cells are crucial for defending against Mycobacterium tuberculosis, but how they function metabolically during prolonged infection is not well understood. By analyzing single-cell RNA sequencing data, researchers found a significant decrease in the genes involved in the electron transport chain across various myeloid cell types as the disease progressed in mice.

This shift in gene expression was linked to alterations in immune and metabolic pathways, such as reduced antigen presentation, interferon responses, protein synthesis, and glycolysis. When the Complex I component of the mitochondria in macrophages was removed (using Ndufs4 knockdown), it led to lower MHC-II surface expression, an abnormal inflammatory gene expression, and hindered control of Mtb replication.

Moreover, examining single-cell transcriptomic data from human household contacts exposed to Mtb revealed a similar transcriptional pattern in individuals who tested positive for IGRA, indicating that mitochondrial respiratory remodeling might play a role in human tuberculosis. In summary, the study reveals that mitochondrial bioenergetic capability is essential for macrophage effector functions during chronic Mtb infection, and restoring mitochondrial function could potentially enhance protective responses in TB patients.