From glucolipotoxicity to cardiorenal injury: mitophagy imbalance in the cardiovascular–kidney–metabolic syndrome continuum

Cardiovascular–kidney–metabolic (CKM) syndrome is a progressive systemic disease driven by the interplay among metabolic abnormalities, chronic kidney disease, and cardiovascular disease. It is characterised by a high prevalence, complex pathophysiological mechanisms, and extensive multi-organ involvement. Currently, clinical management of CKM remains largely focused on individual organ systems, with limited consideration of the syndrome as an integrated entity. This fragmented approach contributes to suboptimal clinical outcomes and imposes a substantial medical and societal burden. The heart and kidneys are highly energy-demanding organs whose structural and functional integrity depends largely on mitochondrial energy production and metabolic homeostasis. Mitophagy is a central component of mitochondrial quality control that maintains cellular homeostasis under physiological conditions by selectively eliminating damaged mitochondria. However, in CKM, impaired mitophagy or excessive mitophagy activation can compromise mitochondrial homeostasis, leading to energy deficiency, sterile inflammation, cell death, tissue fibrosis, and organ dysfunction. Thus, mitophagy may shift from an adaptive protective mechanism to a pathogenic driver of cardiac and renal injury and disease progression. Maintaining mitophagy homeostasis is therefore critical for alleviating early metabolic disturbances, limiting cardiac and renal target-organ damage during disease progression, and delaying CKM advancement. Based on these findings, this review focuses on the mechanistic role of mitophagy dysregulation in CKM progression. Specifically, during the early stages of CKM, glycolipid toxicity-driven metabolic stress disrupts mitophagy homeostasis in the heart and kidneys, impairing mitochondrial quality control in these organs. Subsequent mitophagy imbalance in renal tubular epithelial cells, podocytes, and cardiomyocytes further induces oxidative stress, inflammatory responses, cell death, and tissue fibrosis, ultimately leading to structural and functional impairment of the heart and kidneys. Furthermore, impaired mitochondrial quality control in the kidneys promotes the release of mitochondrial damage-associated molecular patterns, inflammatory mediators, and uraemia-related signals. These factors further amplify myocardial inflammation, fibrosis, and heart failure progression through innate immune pathways, including cGAS–STING, TLR9–NF-κB, and NLRP3 signalling. This review provides an integrated perspective on the pathological progression of CKM and offers a theoretical basis for comprehensive intervention strategies aimed at restoring mitochondrial quality control rather than simply enhancing or suppressing mitophagy.