Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification

Abstract

Highlights What are the main findings? Mitochondrial dysfunction acts as a central driver of aging-associated meta-inflammation by promoting mtROS production, mtDNA release, impaired mitophagy, altered NAD+ metabolism, and activation of NF-κB, NLRP3, cGAS–STING, and SASP pathways. PDK4 emerges as a mitochondrial metabolic checkpoint that restricts pyruvate oxidation, favors lactate accumulation, and may connect altered fuel metabolism to NOX1-derived ROS, SASP activity, and inflammatory amplification. What are the implications of the main findings? The PDK4–PDH axis provides a useful framework for understanding how mitochondrial fuel restriction may contribute to chronic inflammation across aging tissues, including skeletal muscle, adipose tissue, brain, and kidney. Therapeutic strategies that restore mitochondrial fuel flux, improve mitophagy, regulate redox balance, and normalize maladaptive PDK4 activity may help reduce meta-inflammation and preserve healthspan, although clinical translation requires tissue- and context-specific validation. Abstract 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-κB, NLRP3 inflammasome, cGAS–STING, 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.