Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.

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

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.

Recent Insights into Mitochondrial Dysfunction-Driven Cellular Senescence in Chronic Kidney Disease

: Chronic kidney disease (CKD) poses a significant global health challenge, with the accumulation of senescent cells contributing to its pathogenesis. This review synthesizes recent advances highlighting mitochondrial dysfunction as a pivotal driver of cellular senescence in CKD progression. We delineate how CKD-specific pathological insults—such as uremic toxins and metabolic stress—compromise mitochondrial integrity, triggering a cascade of interconnected failures: dysregulation of mitochondrial quality control (impaired biogenesis via PGC-1 α suppression, disrupted dynamics, and deficient mitophagy) leads to the persistence of damaged organelles. Concurrent bioener-getic decline from compromised oxidative phosphorylation and elevated reactive oxygen species (ROS) production further exacerbates cellular stress. These dysfunctional mitochondria subsequently serve as signaling platforms, activating DNA damage responses and innate immune pathways (e.g., NLRP3 inflammasome, cGAS-STING) that amplify the senescence-associated secretory phenotype (SASP). This process establishes a self-perpetuating cycle of inflammation, paracrine senescence, and fibrosis. Emerging therapeutic strategies focused on restoring mitochondrial homeostasis—including targeted antioxidants, modulators of mitochondrial quality control, and metabolic regulators— show promising results in preclinical models for attenuating renal cellular senescence. Consequently, targeting the mitochondrial-senescence axis offers a novel and compelling therapeutic avenue to mitigate CKD progression.

The central role of mitochondrial pathology in sepsis-induced cardiomyopathy: from molecular mechanisms to clinical translation

Sepsis-induced cardiomyopathy (SIC) affects approximately 50% of severe sepsis patients, with mortality rates approaching 80%. This review examines mitochondrial pathology as the central orchestrator of SIC progression. Mitochondrial dysfunction encompasses impaired oxidative phosphorylation (OXPHOS), causing bioenergetic failure; mitochondrial DNA (mtDNA) release activating cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes, Toll-like receptor 9, and NOD-like receptor family pyrin domain containing 3 pathways; ETC dysfunction generating explosive reactive oxygen species (ROS); defective mitophagy leading to damaged mitochondria accumulation; and disturbed mitochondrial dynamics with excessive fission and suppressed fusion. Intercellular mitochondrial transfer through tunneling nanotubes (TNTs) exhibits paradoxical dual effects. Mitochondria-targeted antioxidants selectively accumulate within mitochondria to scavenge ROS and preserve membrane potential. Nrf2 activators enhance endogenous antioxidant defenses. Melatonin modulates mitochondrial function through Ripk3 inhibition. Clinical translation faces substantial obstacles due to sepsis heterogeneity, animal model limitations, and disease complexity. This review integrates mitochondrial biology, immunometabolism, and translational medicine to identify promising directions for improving patient outcomes.

Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics.

Beyond their canonical role in bioenergetics, mitochondria are now recognized as critical signaling platforms that orchestrate innate immune responses. Central to this function is mitochondrial dynamics-the controlled equilibrium between fission and fusion-which serves as a critical structural and thermodynamic checkpoint for cellular fate and immunological status. A substantial body of evidence indicates that pathological mitochondrial fission, frequently driven by Dynamin-related protein 1 (Drp1), is a hallmark of numerous inflammatory conditions. Mechanistically, fragmented mitochondria release damage-associated molecular patterns (DAMPs) and induce acute ATP suppression, metabolically "licensing" NLRP3 activation by collapsing the ATP hydrolysis potential (ΔGATP). Recent breakthroughs have redefined this axis, distinguishing between physical damage and metabolic triggers, such as pyrimidine imbalance via the YME1L-SLC25A33 axis. Furthermore, the immunogenicity of DAMPs is strictly context-dependent; oxidized or "fragile" mtDNA containing ribonucleotides act as hyper-immunogenic ligands for cytosolic sensors like cGAS-STING. Emerging evidence further highlights that endosomal-mitochondrial crosstalk, intercellular mitochondrial transfer, and lipid-driven metabolic rewiring profoundly govern macrophage polarization and tissue homeostasis. Conversely, promoting mitochondrial fusion and robust quality control preserves organellar integrity and attenuates inflammatory cascades. This review critically synthesizes current literature, deconstructing the molecular linkages between organelle structure and metabolic signaling. By exploring the consequences in sepsis, neuroinflammation, osteoarthritis, and cancer, this treatise evaluates the pharmacological potential of modulating mitochondrial dynamics-ranging from direct Drp1 inhibitors and unfractionated heparin to metabolic stabilizers (e.g., GLP-1 receptor agonists), multi-pronged disruptors (e.g., Antimycin A), targeted nanomedicine, and communication-driven mitochondrial transplantation-positioning this axis as a promising frontier for precision pharmacology.

Mitochondrial Integrated Stress Response (mtISR): Mechanistic Basis and Emerging Roles in Skeletal Muscle Pathophysiology

Mitochondria are dynamic organelles that maintain cellular homeostasis through complex mitonuclear communication networks. Among the retrograde signaling pathways linking mitochondrial dysfunction to nuclear gene expression, the mitochondrial integrated stress response (mtISR) has emerged as an important adaptive mechanism, although its chronic activation may contribute to disease progression. It is triggered by various stressors, including mitochondrial DNA (mtDNA) damage, impaired protein import, and metabolic imbalance and is primarily mediated through the eukaryotic translation initiation factor 2 alpha (eIF2α) kinases heme-regulated inhibitor kinase (HRI) and general control nonderepressible 2 (GCN2). Activation of this pathway suppresses global translation while selectively promoting activating transcription factor 4 (ATF4)-dependent transcriptional programs, leading to metabolic remodeling and induction of systemic mitokines. Although mtISR has been characterized in primary mitochondrial myopathies, secondary mitochondrial dysfunction in neuromuscular disorders suggests that mtISR-related pathways may also be activated in these conditions. This review summarizes the molecular mechanisms of mtISR and discusses its roles in skeletal muscle pathology.

The organellar biology of aging: A mitochondrial vantage