Loss of Mitochondrial Respiratory Capacity Reshapes Myeloid Cell Function during Mycobacterium tuberculosis infection
- 1Vanderbilt University Medical Center
Abstract
Myeloid cells are essential mediators of host defense against Mycobacterium tuberculosis (Mtb), yet the metabolic programs that sustain their function during chronic infection remain poorly defined. Here, using scRNA-seq we identified a striking, coordinated decline in mitochondrial electron transport chain gene expression across diverse myeloid populations as Mtb disease progressed in mice. This transcriptional remodeling was associated with broad changes in immune and metabolic pathways, including reduced antigen presentation, interferon responses, protein synthesis, and glycolysis. Accordingly, loss of Complex I in macrophages (Ndufs4 knockdown) reduced MHC-II surface expression, dysregulated inflammatory gene expression, and limited control of Mtb replication. Finally, analysis of single-cell transcriptomic data from Mtb-exposed human household contacts identified an almost identical transcriptional program enriched in IGRA+ individuals, supporting a role for mitochondrial respiratory remodeling in human TB. Together, these findings demonstrate that mitochondrial bioenergetic competence is required to sustain macrophage effector function during chronic Mtb infection and suggest that mitochondrial restoration may boost protective responses in TB patients.
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BibTeX
@misc{martinez2026loss,
title = {{Loss of Mitochondrial Respiratory Capacity Reshapes Myeloid Cell Function during Mycobacterium tuberculosis infection}},
author = {E. L. Martinez and C. J. Mabry and A. K. Coleman and M. S. Osborne and J. D. Simmons and S. Hahn and J. B. Huskey and K. S. Armijo and T. Newbolt and J. R. Davis and L. Zhou and S. Kalams and D. Mogilenko and K. L. Patrick and R. O. Watson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749543},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749543v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Loss of Mitochondrial Respiratory Capacity Reshapes Myeloid Cell Function during Mycobacterium tuberculosis infection
AU - E. L. Martinez
AU - C. J. Mabry
AU - A. K. Coleman
AU - M. S. Osborne
AU - J. D. Simmons
AU - S. Hahn
AU - J. B. Huskey
AU - K. S. Armijo
AU - T. Newbolt
AU - J. R. Davis
AU - L. Zhou
AU - S. Kalams
AU - D. Mogilenko
AU - K. L. Patrick
AU - R. O. Watson
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749543
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749543v1
AB - Myeloid cells are essential mediators of host defense against Mycobacterium tuberculosis (Mtb), yet the metabolic programs that sustain their function during chronic infection remain poorly defined. Here, using scRNA-seq we identified a striking, coordinated decline in mitochondrial electron transport chain gene expression across diverse myeloid populations as Mtb disease progressed in mice. This transcriptional remodeling was associated with broad changes in immune and metabolic pathways, including reduced antigen presentation, interferon responses, protein synthesis, and glycolysis. Accordingly, loss of Complex I in macrophages (Ndufs4 knockdown) reduced MHC-II surface expression, dysregulated inflammatory gene expression, and limited control of Mtb replication. Finally, analysis of single-cell transcriptomic data from Mtb-exposed human household contacts identified an almost identical transcriptional program enriched in IGRA+ individuals, supporting a role for mitochondrial respiratory remodeling in human TB. Together, these findings demonstrate that mitochondrial bioenergetic competence is required to sustain macrophage effector function during chronic Mtb infection and suggest that mitochondrial restoration may boost protective responses in TB patients.
ER -