Human cardiac organoids (cardiomorphs) that recapitulate the multicellular complexity and developmental maturation of native myocardium enable the first three-dimensional tissue model of Kearns-Sayre syndrome mitochondrial cardiomyopathy and reveal that the FDA-approved β1-adrenergic antagonist Betaxolol restores cardiac function through a mutation-agnostic mechanism coupling selective mitophagy of dysfunctional mitochondria with biogenesis of functional organelles, establishing a generalizable therapeutic principle for mitochondrial disease.

The human heart is among the most complex tissues to replicate in vitro, with vascular, neuronal, and immune elements shaping its development and function. Here we describe cardiomorphs, self-organising human cardiac organoids that recapitulate the cellular diversity, structural organisation, vascularisation, and innervation of the myocardium and mature along a developmental trajectory from early cardiogenesis to adult tissue. Using patient-derived cardiomorphs, we establish the first three-dimensional human tissue model of Kearns–Sayre syndrome (KSS), a rare mitochondrial disorder characterised by large-scale mtDNA deletions. KSS-cardiomorphs faithfully reproduce disease-associated metabolic, contractile, and ultrastructural hallmarks. Leveraging this platform, we identify Betaxolol, an FDA-approved selective β1-adrenergic antagonist, as a modulator of mitochondrial quality control. Betaxolol increases intracellular oxygenation, selectively eliminates dysfunctional mitochondria via mitophagy, and promotes biogenesis of functional organelles, restoring contractility in KSS tissues. This dual-action, mutation-agnostic mechanism suggests a therapeutic principle with broad relevance to mitochondrial disease, cardiac pathology, and age-associated decline.