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

Cellular Senescence in Diabetic Cardiomyopathy: Mechanistic Insights and Therapeutic Perspectives.

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

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.

Remodeling lipid and mitochondrial homeostasis: a novel mechanism by which polydatin attenuates renal tubular senescence in chronic kidney disease.

Tubular cell senescence is a well-recognized key driver of chronic kidney disease (CKD) pathogenesis, which imposes a substantial global health burden. Polydatin (PD) is a natural polyphenol derived from Polygonum cuspidatum, its novel potential to modulate tubular cell senescence in CKD-specifically through remodeling lipid dysfunction and restoring mitochondrial homeostasis-remains unelucidated. Our study focused on unraveling the core molecular mechanisms underlying PD driven therapeutic effects in CKD, with SIRT3 as a key target validated by tubule-specific depletion strategies in vivo. PD treatment significantly ameliorates renal dysfunction, attenuates tubular injury, and mitigates interstitial fibrosis in CKD, with consistent renoprotective effects confirmed in vitro. Transcriptomic analyses identified lipid metabolism remodeling and mitochondrial homeostasis restoration as core pathways regulated by PD, with the SIRT3/SOD2 axis emerging as a central regulatory hub. Mechanistically, PD restores SIRT3 expression, which in turn enhances SOD2 deacetylation, boosts antioxidant capacity, reverses lipid dysfunction, and ultimately reduces mitochondrial reactive oxygen species (ROS) accumulation and mitochondrial damage. Notably, PD effectively suppresses the DNA damage response via reducing γH2AX foci formation, thereby alleviating tubular cell senescence (evidenced by decreased p21 expression and SA-β-gal activity in vivo and in vitro). Critically, tubule-specific SIRT3 knockout or siRNA-mediated knockdown abrogated protective effects modulated by PD, underscoring SIRT3 as an essential mediator of its therapeutic actions. Collectively, our study unveils that PD rewires lipid metabolism, restores mitochondrial homeostasis, and activates the SIRT3/SOD2 axis to mitigate DNA damage and suppress tubular senescence, thereby halting CKD progression. These findings position PD as a promising therapeutic candidate for senescence-associated kidney diseases.

Redox-Mediated Mitochondrial Dysfunction as a Common Pathogenic Axis in Acute Kidney Injury and Chronic Kidney Disease

Acute kidney injury (AKI), chronic kidney disease (CKD), and diabetic kidney disease (DKD) are interconnected disorders linked by shared mechanisms involving redox imbalance and mitochondrial dysfunction. This review summarizes current evidence on the role of excessive reactive oxygen species (ROS) production, impaired oxidized nicotinamide adenine dinucleotide (NAD+) metabolism, altered mitochondrial bioenergetics, disrupted mitochondrial dynamics, and defective mitochondrial quality control pathways, including mitophagy and the mitochondrial unfolded protein response (UPRmt), in kidney disease progression. Experimental and clinical studies indicate that these mechanisms contribute to inflammation, fibrosis, apoptosis, and maladaptive repair, promoting progression from AKI to CKD and worsening DKD. The review also discusses emerging biomarkers and therapeutic strategies targeting oxidative stress and mitochondrial dysfunction. Overall, redox-mediated mitochondrial injury represents a shared pathogenic axis and a potential therapeutic target across kidney diseases.

Complosome as a key modulator of cellular senescence, aging and age-related diseases.

Aging is characterized by progressive physiological decline and accumulation of senescent cells that drive chronic "inflammaging" through the senescence-associated secretory phenotype (SASP). The complement system, traditionally viewed as a systemic extracellular defense mechanism, is now recognized as an essential intracellular network (the complosome). This review synthesizes current research on how intracellular C3 (intC3), and intracellular C5 (intC5) in certain contexts engage in extensive crosstalk with the mTOR, NF-κB, and AMPK pathways to modulate core cellular processes. We detail how intC3 intersects with multiple canonical hallmarks of aging-including cellular senescence, mitochondrial dysfunction, proteostasis loss, genomic instability, epigenetic alterations, altered intercellular communication, stem cell exhaustion, and deregulated nutrient sensing. Furthermore, we examine organ-specific consequences of intC3 dysregulation across the aging brain, liver, eye, kidney, vasculature, lung, and immune system, as well as cancer. Finally, we discuss therapeutic strategies-including complement inhibitors, senolytics, senomorphics, RNA interference, proteolysis targeting chimeras (PROTACs), and nanotechnology-enabled delivery-and outline critical gaps in compartment-specific tools, conditional knockouts, and longitudinal models. Precision strategies that preserve systemic complement function while selectively modulating intracellular pools will be essential to translate complosome biology into durable interventions for age-related diseases.

Immuno-metabolic reprogramming in pulmonary fibrosis: Emerging therapeutic targets beyond inflammation.

Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive extracellular matrix deposition, tissue remodeling, and irreversible loss of lung function. Although inflammation contributes to disease progression, increasing evidence indicates that immunometabolic reprogramming is a central driver of fibrotic persistence. Alterations in glycolysis, mitochondrial function, lipid metabolism, and redox homeostasis actively regulate immune responses, fibroblast activation, and epithelial cell dysfunction, thereby sustaining a profibrotic microenvironment. This review synthesizes current advances in understanding how metabolic pathways regulate immune and structural cell behavior during pulmonary fibrosis. Particular emphasis is placed on metabolic checkpoints, including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and nicotinamide adenine dinucleotide (NAD+)-dependent signaling, which integrate metabolic and inflammatory responses. We further discuss how mitochondrial dysfunction, hypoxia-inducible factor-1α (HIF-1α), reactive oxygen species (ROS), cellular senescence, and metabolic memory contribute to disease persistence. Emerging evidence supports metabolic crosstalk between immune cells and fibroblasts as a key mechanism driving fibrotic remodeling. Finally, we evaluate therapeutic strategies targeting immunometabolic pathways and discuss current translational challenges, including cellular heterogeneity, pathway redundancy, and limited clinical validation. Collectively, this review highlights immunometabolic regulation as a promising therapeutic framework and identifies opportunities for precision-based interventions in pulmonary fibrosis.