Mitochondria-derived vesicles with bioenergetic units from brown adipose tissue attenuate cardiac remodeling post-myocardial infarction

Post-myocardial infarction remodeling is a major cause of heart failure, with contributions from multiple organs. Brown adipose tissue protects against cardiovascular disease, but the mediators of brown adipose tissue-heart crosstalk and their roles in cardiac remodeling remain elusive. Here, we show that mitochondria-derived vesicles from brown adipose tissue transfer to cardiac macrophages and attenuate pathological remodeling via anti-inflammatory effects. Vesicles containing mitochondrial membranes, rather than mitochondrial matrix, mobilize from brown adipose tissue to the heart in response to stress. VPS35 translocation to mitochondria drives protein packaging into mitochondria-derived vesicles for secretion through extracellular vesicle trafficking machinery. Becn1 deficiency impairs VPS35 translocation, alters mitochondria-derived vesicle cargo, and abolishes brown adipose tissue-mediated cardioprotection. Proteomics identifies mitochondrial respiratory chain complex V as a hallmark of protective mitochondria-derived vesicles. These vesicles enhance reparative cytokine production and oxidative phosphorylation rewiring in macrophages. Purified mitochondria-derived vesicles markedly improve remodeling in male mice. Our study uncovers an interorgan transfer of bioenergetic units that contributes to tissue repair.