Cardiovascular-kidney-metabolic syndrome as a mitochondrial systems disorder.

Abstract

Cardiovascular-kidney-metabolic (CKM) syndrome is a multisystem disorder in which obesity, diabetes, chronic kidney disease, and cardiovascular disease reinforce one another through shared pathobiological characteristics and bidirectional organ crosstalk. Rather than representing the mere coexistence of diseases, CKM syndrome can be understood as a mitochondrial systems disorder. In energy-intensive tissues such as the myocardium and renal tubules, chronic haemodynamic stress, substrate excess, hypoxia and neurohormonal activation converge on mitochondrial programmes governing oxidative phosphorylation, redox balance, organelle dynamics and quality control. Disruption of these programmes, including impaired fatty acid oxidation, suppressed biogenesis, defective mitophagy and mitochondrial DNA instability, reduces bioenergetic reserve and promotes reactive oxygen species generation, inflammatory signalling and progressive organ dysfunction. Mitochondrial dysfunction in other metabolic tissues further amplifies these processes. In the liver, reduced fatty acid oxidation promotes steatosis, insulin resistance and the release of lipids, whereas in skeletal muscle and adipose tissue, impaired oxidative capacity and insulin resistance increases lipid spillover and systemic inflammation. Mitochondria-derived signals - including FGF21, GDF15, succinate and circulating mitochondrial DNA - enable bidirectional communication between organs, reinforcing multi-organ decline in a positive-feedback loop. Advancing our understanding of mitochondrial dysfunction and inter-organ communication may provide new mechanistic insights into CKM syndrome progression and inform the development of mitochondria-targeted therapeutic strategies.