{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:45:29Z","timestamp":1787240729669,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Merit Review Award, Department of Veterans Health","award":["I01BX001786"],"award-info":[{"award-number":["I01BX001786"]}]},{"name":"NIH","award":["I01BX001786"],"award-info":[{"award-number":["I01BX001786"]}]},{"name":"CF Foundation","award":["I01BX001786"],"award-info":[{"award-number":["I01BX001786"]}]},{"name":"NIH","award":["I01BX001786"],"award-info":[{"award-number":["I01BX001786"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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-1\u03b1) 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-1\u03b1-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-1\u03b1, 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-1\u03b1 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.<\/jats:p>","DOI":"10.3390\/ijms26199270","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T10:27:53Z","timestamp":1758623273000},"page":"9270","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Zinc Promotes Mitochondrial Health Through PGC-1alpha Enhancing Bacterial Clearance in Macrophages Infected with Mycobacterium avium Complex"],"prefix":"10.3390","volume":"26","author":[{"given":"Ruxana T.","family":"Sadikot","sequence":"first","affiliation":[{"name":"VA Nebraska Western Iowa Health Care System, Omaha, NE 68105, USA"},{"name":"Division of Pulmonary, Critical Care & Sleep, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9617-5555","authenticated-orcid":false,"given":"Prabagaran","family":"Narayanasamy","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care & Sleep, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Yuan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care & Sleep, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5232-6083","authenticated-orcid":false,"given":"Deandra","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care & Sleep, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Department of Pharmacy and Science, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9977-2857","authenticated-orcid":false,"given":"Daren L.","family":"Knoell","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care & Sleep, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Department of Pharmacy and Science, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41392-023-01679-y","article-title":"Cellular zinc metabolism and zinc signaling: From biological functions to diseases and therapeutic targets","volume":"9","author":"Chen","year":"2024","journal-title":"Signal Transduct. 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