Context-dependent mitochondrial transfer in cardiovascular disease: mechanisms and therapeutic translation

Cardiovascular diseases are frequently driven by mitochondrial dysfunction, yet mitochondrial homeostasis extends beyond cell-autonomous quality control to intercellular mitochondrial transfer. Transferred mitochondria can restore bioenergetics and support tissue repair, whereas damaged mitochondrial material can propagate oxidative stress, inflammation and regulate cell death. This duality has limited therapeutic interpretation because mitochondrial transfer is often treated as uniformly beneficial or harmful. This review examines how the identity and functional state of transferred mitochondrial material, donor state, transfer route, recipient metabolism, inflammatory context and intracellular processing shape cardiovascular outcomes. Across major cardiovascular settings, we compare the source and form of the transferred material, the transfer or administration route, recipient responses and the strength of evidence for benefit or harm. These settings include acute ischemia and reperfusion injury, cardiomyopathy, heart failure, vascular dysfunction, pulmonary hypertension, critical illness related myocardial injury and donor heart preservation. Endogenous mitochondrial transfer is considered separately from mitochondrial transplantation, which involves the deliberate administration of isolated mitochondrial preparations. Benefit is most plausible when mitochondria with preserved respiratory function reach salvageable cells within a permissive metabolic window and recipient quality control systems remain functional. Conversely, oxidatively damaged mitochondria, metabolic mismatch or defective clearance can convert transfer into an inflammatory and cytotoxic burden. We therefore frame mitochondrial transfer as a pharmacologically tractable network with distinct intervention nodes, rather than as a single organelle-replacement strategy. Translational opportunities include quality-controlled mitochondrial transplantation, mitochondria-enriched extracellular vesicles, targeted or biomaterial-assisted delivery, selective blockade of pathological transfer and enhancement of macrophage-mediated clearance. Future development should couple product identity, purity, potency and safety testing with mechanism-based patient stratification, recipient-cell tracing and clinically relevant long-term endpoints. This context-guided approach may support precise mitochondria-based therapeutics while defining when mitochondrial supplementation should be promoted, redirected or avoided.