Document Type
Article
Journal Title
International Journal of Molecular Sciences
Publication Date
2025
Volume
26
Abstract
Mitochondria are increasingly recognized as important contributors to immune function, in addition to energy production. They exert this influence through modulation of various signaling pathways that regulate cellular metabolism and immune function in response to pathogens. Peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PGC-1α) is the primary transcription factor and regulator involved in mitochondrial biogenesis. Long known to be involved in immune function, zinc (Zn) is also required for proper mitochondrial function. It is increasingly recognized that many cellular immunometabolic activities are also Zn-dependent. Taken together, we investigated the role of Zn deficiency, both dietary and genetically induced, and Zn supplementation in PGC-1α-mediated macrophage mitochondrial biogenesis and immune function following infection with Mycobacterium avium complex (MAC). Our novel findings show that Zn is an important regulator of PGC-1α, TFAM and mitochondrial biogenesis, leading to enhanced bacterial phagocytosis and bacterial killing in macrophages. Mechanistically, we show that the Zn importer ZIP8 (Zrt/Irt-like protein) orchestrates Zn-mediated effects on PGC-1α and mitochondrial function. Taken together, defective Zn biodistribution may increase susceptibility to infection, whereas Zn supplementation may provide a tractable host-directed therapy to enhance the innate immune response in patients vulnerable to MAC infection.
MeSH Headings
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Macrophages, Animals, Mitochondria, Zinc, Mice, Mycobacterium avium Complex, Mycobacterium avium-intracellulare Infection, Phagocytosis, Mice, Inbred C57BL, Transcription Factors, Humans, DNA-Binding Proteins
DOI Link
ISSN
1422-0067
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Sadikot, Ruxana; Narayanasamy, Prabagaran; Yuan, Zhihong; Smith, Deandra R.; and Knoell, Daren L., "Zinc Promotes Mitochondrial Health Through PGC-1alpha Enhancing Bacterial Clearance in Macrophages Infected with Mycobacterium avium Complex" (2025). Journal Articles: Pulmonary & Critical Care Med. 94.
https://digitalcommons.unmc.edu/com_pulm_articles/94
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