Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification
Aug 2026· Cells· Vol 15, pp. 1404· 0 citations· 64 references
Medicine
TL;DR
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, and therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan are evaluated.
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.
This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming, and critically examines how mitochondria act as signaling hubs for inter-organ crosstalk.
C. Han, Zilian Zhang, Yafeng Song· Gerontology· 0 citations
Mitochondrial dysfunction has emerged as a convergent pathogenic mechanism across inflammatory and degenerative disorders, functioning not as a passive consequence but as an active amplifier of tissue injury, immune dysregulation, and impaired repair. Consistently observed mitochondrial abnormalities include excessive reactive oxygen species production, impaired oxidative phosphorylation, defective mitophagy, altered fission-fusion dynamics, and release of mitochondrial danger-associated molecular patterns, particularly cell-free mitochondrial DNA (cf-mtDNA), which serves both as a proinflammatory mediator and a potential circulating biomarker of disease activity. These alterations create self-reinforcing networks in which mitochondrial stress promotes innate immune activation, sustains inflammatory signaling, and accelerates structural or functional decline in vulnerable tissues. Mitochondria-targeted pharmacology has expanded rapidly, encompassing organelle-directed antioxidants, modulators of mitochondrial quality control, biogenesis or metabolic enhancers, nano-enabled delivery platforms, and emerging mitochondrial replacement strategies. Despite strong mechanistic appeal and encouraging preclinical data, clinical translation remains limited by the absence of validated pharmacodynamic biomarkers, an incomplete understanding of disease endotypes, inconsistent tissue target engagement, delivery barriers to mitochondria-rich compartments, and poor predictive value of animal models for human disease biology. The cf-mtDNA and related mitochondrial signatures are increasingly attracting attention for patient stratification, phenotyping, and therapeutic monitoring, although assay standardization remains unresolved. This review focuses on the core mechanisms that link mitochondrial dysfunction to disease progression. It also examines biomarker development and the major barriers to translation. Emerging approaches such as nanotechnology and mitochondrial replacement are discussed as supplementary strategies, not as the main focus of the review.
L. Elabbasy· Current opinion in pharmacol...· 0 citations
Metabolic dysfunction-associated fatty liver disease (MASLD) represents the most prevalent chronic liver disorder globally, with pathogenesis closely linked to insulin resistance, obesity, and gut microbiota dysbiosis. Mitochondrial dysfunction is central to MASLD progression, and mitophagy-a selective form of autophagy that clears damaged mitochondria-plays a crucial role in maintaining cellular homeostasis. This review systematically delineates the molecular mechanisms, regulatory networks, and therapeutic implications of mitophagy in MASLD. We first outline the core machinery of mitophagy, encompassing both ubiquitin-dependent and ubiquitin-independent pathways. We then discuss how impaired mitophagy drives the disease progression of MASLD from the perspective of different hepatic cell types. Furthermore, we summarize the multilayered upstream regulatory network governing mitophagy in the context of MASLD, involving key signaling pathways, metabolic reprogramming, inflammatory cues, epigenetic modifications, and intercellular crosstalk. Finally, we examine therapeutic strategies targeting mitophagy-including clinical and preclinical agents, natural compounds, physical interventions, and emerging technologies-and highlight the challenges posed by its dualistic nature. Moving forward, integrating spatiotemporal dynamics with precision targeting will be essential to translate mitophagy modulation from mechanistic insight into viable clinical therapies for MASLD.
Alzheimer's disease (AD) is increasingly recognized as a disorder in which amyloid-β deposition and tau pathology interact with neuroinflammation and metabolic dysregulation. Although mitochondrial dysfunction, redox imbalance, and NLRP3 inflammasome activation have each been implicated in AD pathogenesis, their mechanistic continuity within microglial immunometabolic reprogramming remains insufficiently defined. This narrative review integrates mechanistic, preclinical, and human-relevant evidence to propose a stage-dependent mitochondrial dysfunction-redox imbalance-NLRP3 inflammasome axis. We discuss how AD-related stimuli shift microglia toward a pro-inflammatory metabolic phenotype; how impaired mitochondrial quality control promotes reactive oxygen species generation and oxidized mitochondrial DNA release; and how these signals facilitate NLRP3 inflammasome activation and sustained inflammatory amplification. We further summarize therapeutic strategies targeting upstream mitochondrial homeostasis, intermediate metabolic-redox coupling, and downstream NLRP3 signaling, while emphasizing the translational limitations and biomarker needs. We conclude that this proposed axis provides a testable stage-dependent framework for interpreting chronic, self-amplifying neuroinflammation in AD and may inform biomarker-guided, combinatorial therapeutic strategies.
Siyu Li, Juntao Jin, Yingying Liu et al.· Journal of Alzheimer's Disea...· 1 citation
Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognized as a disorder of inter-organelle communication, in which the lipid droplet (LD)–mitochondria interface serves as a central metabolic hub. Under physiological conditions, this interface couples LD lipolysis to mitochondrial β-oxidation, ensuring that fatty-acid release matches energy demand. In MASH, chronic nutrient excess disrupts this coupling, driving the accumulation of lipotoxic metabolites, activating innate immune pathways, and perpetuating hepatocellular injury and inflammation. Among the proteins proposed to operate at this LD-mitochondria interface, hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) has emerged as a particularly compelling candidate. A loss-of-function human genetic variant is associated with reduced risk of chronic liver disease, motivating therapeutic development; however, whether HSD17B13 directly governs physical organelle apposition or merely influences lipid flux remains unresolved, highlighting a key gap between human genetic evidence and experimental models. This review synthesizes current understanding of the molecular organization of the LD-mitochondria axis, critically examines the proposed scaffolding and enzymatic functions of HSD17B13, and discusses the therapeutic potential of restoring organelle communication as a unified strategy in MASH. We conclude that targeting inter-organelle interfaces, rather than isolated metabolic reactions, offers a genetically supported and mechanistically rational path forward.
Shanzab Noor, Yuan Tian, Wen Su· Frontiers in Cell and Develo...· 0 citations
Metabolic Syndrome (MetS) is a complex and multifactorial condition characterized by insulin resistance, visceral obesity, dyslipidemia, hypertension, and chronic low-grade inflammation, all of which contribute to increased cardiovascular risk. Central to its pathophysiology is metainflammation, a persistent inflammatory state closely linked to oxidative stress and mitochondrial dysfunction. This review aims to provide an integrated and updated overview of the interplay between metainflammation, oxidative stress, mitochondrial dysfunction, and organokine signaling in the development and progression of MetS and its cardiovascular complications. Current evidence indicates that mitochondrial dysfunction plays a pivotal role by promoting excessive production of reactive oxygen species (ROS), impairing ATP synthesis, and disrupting redox balance, thereby exacerbating insulin resistance and endothelial dysfunction. In parallel, dysregulated secretion of organokines—including adipokines, myokines, hepatokines, cardiokines, osteokines, and renokines—alters interorgan communication and amplifies pro-inflammatory and atherogenic pathways. Additionally, gut microbiota contributes to metabolic homeostasis through the production of short-chain fatty acids, whereas dysbiosis is associated with worsening metabolic parameters. Collectively, these interconnected mechanisms establish a self-perpetuating cycle that drives metabolic dysfunction and cardiovascular disease progression. This review highlights the central role of the metainflammation–mitochondrial dysfunction axis and emphasizes the importance of organokine-mediated crosstalk as a key regulator of systemic metabolism. Targeting these pathways may represent a promising strategy for the prevention and management of MetS and its associated complications.
Ana Flávia Pontes Sodré, Lucca Gonsales Rodrigues, K. P. Sloan et al.· International Journal of Mol...· 0 citations