Heart failure and mitochondrial dynamics: Role of intracellular angiotensin and emerging therapeutics

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide despite significant advances in neurohumoral therapies targeting the renin-angiotensin-aldosterone (RAAS). Although RAAS inhibition improves survival and limits adverse cardiac remodelling in failing hearts, mitochondrial dynamic dysfunction persists in a larger proportion of treated patients, indicating an intracellular signalling mechanism that sustains the pathological remodelling in these patients. Emerging evidence shows a shift toward a fission-dominant mitochondrial phenotype, acting as a critical feature of a failing heart. Angiotensin II (Ang II), beyond its classical endocrine actions, activates a network of calcium- and redox-dependent intracellular signalling pathways that converge on the mitochondrial fission machinery. Many of these components are incompletely inhibited by the conventional RAAS blockade, providing a mechanistic basis for RAAS escape and persistent mitochondrial dysfunction. This review highlights the mechanism underlying the temporal stabilization of fission-dominant mitochondrial phenotype, and discusses the opportunity to target mitochondrial dynamics as a complementary therapeutic strategy. Reframing angiotensin signalling through the lens of mitochondrial dysregulated dynamics may help overcome the limitations of current heart failure therapies.