Cardiac FGF21 acts as an endocrine suppressor of female fertility in mitochondrial cardiomyopathy

Cardiomyopathy is clinically associated with female infertility, yet whether the failing heart directly suppresses reproduction has remained unknown. Here we identify a heart–brain endocrine axis in which pathological cardiac stress induces systemic elevation of the mitokine FGF21, which in turn suppresses the hypothalamic-pituitary-gonadal axis and inhibits fertility. In female mice with dilated cardiomyopathy caused by mitochondrial fission deficiency (Mff KO), we observe delayed puberty, anovulation, and hypogonadotropic hypogonadism due to blunted LH secretion and selective suppression of hypothalamic kisspeptin neurons. Exogenous kisspeptin administration restores ovulation despite persistent cardiac dysfunction. Integrated transcriptomics and metabolomics analyses reveal that the signal originates from a cardiac mitochondrial integrated stress response that drives de novo FGF21 expression in the heart. Cardiac-specific Mff re-expression abolishes the signal at its source, while genetic deletion of Fgf21 fully restores puberty and fertility even in the presence of ongoing cardiomyopathy. These findings demonstrate that cardiac-derived FGF21 acts as a key endocrine suppressor of the reproductive axis during heart failure, revealing an inter-organ communication pathway that links cardiac mitochondrial stress to reproductive control.