Recent Insights into Mitochondrial Dysfunction-Driven Cellular Senescence in Chronic Kidney Disease
TL;DR
This review synthesizes recent advances highlighting mitochondrial dysfunction as a pivotal driver of cellular senescence in CKD progression to propose a novel and compelling therapeutic avenue to mitigate CKD progression.
Abstract
: 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.