{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:51:12Z","timestamp":1785919872714,"version":"3.56.0"},"reference-count":63,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health & Welfare, Republic of Korea","award":["RS-2022-KH130590"],"award-info":[{"award-number":["RS-2022-KH130590"]}]},{"award":["RS-2022-KH130590"],"award-info":[{"award-number":["RS-2022-KH130590"]}],"id":[{"id":"https:\/\/ror.org\/00vxgjw72","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korea government","doi-asserted-by":"publisher","award":["RS-2022-NR068984"],"award-info":[{"award-number":["RS-2022-NR068984"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Aging is accompanied by a progressive decline in mitochondrial quality, bioenergetic flexibility, and stress resilience. Aging mitochondria are increasingly recognized as active inflammatory signaling platforms rather than passive targets of cellular damage. Excess mtROS, leaked mtDNA, defective mitophagy, altered NAD+ metabolism, and impaired pyruvate oxidation together create a cellular environment that favors persistent inflammatory activation. These signals engage NF-\u03baB, NLRP3 inflammasome, cGAS\u2013STING, and SASP pathways, allowing mitochondrial stress to spread from organelle dysfunction to tissue-level inflammation. Within this framework, pyruvate dehydrogenase kinase 4 (PDK4) is of particular interest because it directly controls mitochondrial pyruvate entry through inhibition of the pyruvate dehydrogenase complex. By phosphorylating and inhibiting the pyruvate dehydrogenase complex, PDK4 limits mitochondrial pyruvate oxidation and favors lactate accumulation, fatty acid utilization, and redox-inflammatory signaling. Recent work in senescent cells links PDK4-dependent lactate accumulation to NOX1-derived ROS and SASP activity, suggesting a direct route by which altered fuel handling may reinforce inflammation. Here, we review mitochondrial dysfunction as the organizing principle of age-associated meta-inflammation, discuss PDK4 as a central metabolic checkpoint, examine tissue-specific consequences in muscle, adipose tissue, brain, and kidney, and evaluate therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan.<\/jats:p>","DOI":"10.3390\/cells15151404","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T14:16:27Z","timestamp":1785766587000},"page":"1404","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7885-9021","authenticated-orcid":false,"given":"Md Riad","family":"Chowdhury","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui-Hwa","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, CHA Gumi Medical Center, CHA University, Gumi 39295, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2261-7269","authenticated-orcid":false,"given":"In-Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of Aging: An Expanding Universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1038\/s41591-019-0675-0","article-title":"Chronic Inflammation in the Etiology of Disease across the Life Span","volume":"25","author":"Furman","year":"2019","journal-title":"Nat. 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