According to the World Health Organization, cardiovascular diseases remain the leading cause of death worldwide. Despite major advances in pharmacotherapy and surgical interventions, a considerable proportion of patients still progress to chronic cardiac dysfunction, highlighting the need for novel therapeutic strategies that directly target the cellular disturbances underlying disease progression.

Mitochondria play a fundamental role in the cardiovascular system. It is estimated that approximately 30% of the total cardiomyocyte volume is composed of mitochondria, which provide the energy required for cardiac function. Under pathological conditions, mitochondrial dysfunction develops, impairing not only myocardial bioenergetics but also metabolic regulation, while promoting oxidative stress, inflammation, and apoptosis. These alterations in mitochondrial integrity and dynamics precede and perpetuate myocardial damage. In response, several pharmacological approaches have been explored, including dietary supplements aimed at enhancing respiratory chain activity, inducing mitochondrial biogenesis, or acting as mitochondrial antioxidants. Although these approaches yielded promising results in experimental models, clinical trials have produced inconsistent findings. To date, these agents have failed to significantly relieve disease symptoms or effectively slow progression, leaving no satisfactory therapeutic option for mitochondrial disorders and for the imbalance between energy demand and supply characteristic of these conditions. Against this background, mitochondrial transplantation has recently emerged as a novel therapeutic concept in disorders with impaired mitochondrial function. This strategy aims to deliver viable mitochondria to injured tissues, with the goal of restoring cellular bioenergetics while reducing oxidative and apoptotic damage. Although still in the early phases of clinical development, preliminary findings from both animal models and human studies appear highly encouraging.

– Origin of the mitochondrial transplantation concept

The idea of transferring exogenous mitochondria into injured tissues originates from intrinsic cellular mechanisms. Cells in the human body are capable of exchanging mitochondria to ensure adequate energy supply, improve mitochondrial performance, and promote the repair of injured cells. This intercellular mitochondrial transfer may occur through tunneling nanotubes, dendritic projections, release in microvesicles, or even secretion of “naked” mitochondria.

In recent years, experimental studies have demonstrated the feasibility of mitochondrial transplantation. Several cell types—including cardiomyocytes, myoblasts, neurons, and hepatocytes—can internalize exogenous mitochondria when added to culture media. The incorporation of functional mitochondria has been shown to enhance ATP production in a dose-dependent manner, supporting their ability to augment cellular energy capacity. Mechanistic analyses have revealed that mitochondrial uptake occurs via actin-dependent endocytic pathways.

Mitochondria are generally harvested from tissues with high mitochondrial density, such as intercostal skeletal muscle, or, in experimental settings, from cardiac tissue itself. The extraction process requires specific techniques, such as differential centrifugation, to preserve structural and functional integrity. Once isolated, mitochondria may be directly injected into damaged tissues or delivered systemically via intravenous infusion in cases of multiorgan mitochondrial disease. Preclinical studies have confirmed that exogenously isolated and labeled mitochondria can be incorporated into multiple organs, including liver, brain, lungs, skeletal muscle, and kidneys, following systemic administration.

– Experimental and clinical evidence

Most experimental studies conducted to date have focused on acute ischemia–reperfusion injury models, in which freshly isolated autologous mitochondria were administered. In this field, the group led by Dr. McCully at Boston Children’s Hospital pioneered mitochondrial transplantation. Their studies demonstrated that mitochondria locally delivered to the myocardium predominantly remained at the injection sites. Uptake of mitochondria by cardiomyocytes occurred within a very short timeframe (within 2 hours), and functional mitochondria were identified inside myocytes for up to 28 days after intervention, suggesting durable structural integration. In a porcine model, mitochondrial injection into ischemic myocardial regions did not trigger immune responses after 4 weeks of recovery. By contrast, when mitochondria were administered during the reperfusion phase, animals showed decreased creatine kinase and cardiac troponin I concentrations 3 days after intervention, which was accompanied by smaller infarct sizes at 4 weeks. Another study under similar experimental conditions demonstrated that mitochondrial injection into porcine myocardium improved left ventricular developed pressure, end-diastolic pressure, and systolic shortening 120 minutes after reperfusion. Nevertheless, this delivery method presents practical limitations, including the need for multiple injections and direct myocardial manipulations to achieve widespread mitochondrial distribution. To overcome these constraints, intracoronary administration has been explored. Whole-body positron emission tomography demonstrated that transplanted mitochondria were primarily retained within the left ventricle, without significant accumulation in other organs. Under baseline conditions, mitochondrial infusion produced no hemodynamic or heart rate alterations, supporting its safety profile. However, in ischemia–reperfusion models, intracoronary delivery enhanced myocardial contractility, improving left ventricular ejection fraction and fractional shortening 120 minutes after reperfusion. These effects were associated with increased coronary blood flow and reduced infarct size.

Beyond the heart, preclinical studies in other organs have demonstrated broader applicability of mitochondrial transplantation. Systemic delivery of hepatocyte-derived mitochondria reduced lipid accumulation and oxidative stress in diet-induced fatty liver disease models. Similarly, portal vein infusion mitigated paracetamol-induced hepatotoxicity. In pulmonary models, mitochondrial administration via nebulization or through the pulmonary artery improved lung mechanics and attenuated tissue injury after ischemia–reperfusion. In both rat and porcine models, infusion through the renal artery ameliorated tubular injury, lowered plasma creatinine, and improved glomerular filtration rates under ischemia–reperfusion conditions. Direct mitochondrial injection into the brain improved motor performance, reduced infarct volume, and attenuated apoptosis in experimental models of cerebral ischemia, demonstrating that the therapeutic benefits of mitochondrial transplantation extend to multiple tissues affected by mitochondrial damage.

The first clinical application of mitochondrial transplantation was reported by McCully’s team in 2017. At Boston Children’s Hospital, 5 pediatric patients with ischemic myocardial injury were enrolled. These patients had shown no improvement in cardiac function after surgery and required extracorporeal membrane oxygenation (ECMO) support. Autologous mitochondria were harvested from skeletal muscle and delivered into ischemic myocardial regions using a 1 mL syringe with a 28G needle. No arrhythmias or bleeding events related to the epicardial injections were observed. Of the 5 patients, 4 experienced improved ventricular function and were successfully weaned from ECMO support. Currently, 3 clinical trials are underway to evaluate mitochondrial transplantation in larger patient populations across different age groups, aiming to establish its therapeutic potential for ischemic cardiovascular disease.

– Challenges and future perspectives

The growing enthusiasm for mitochondrial transplantation is understandable: few therapeutic strategies have promised so much while involving so little genetic material. Directly targeting the cell’s fundamental energy unit—the mitochondrion—represents a paradigm shift in the management of myocardial injury, particularly in settings where current therapies merely slow progressive decline.

Mitochondrial transplantation offers several advantages in the management of cardiovascular disease

• It directly restores ATP production and reduces intracellular oxidative stress, whereas conventional therapies often act on symptoms or secondary pathways.
  • The use of autologous mitochondria avoids immune activation, providing a favorable safety profile in highly sensitive clinical contexts such as pediatric cardiac surgery or acute myocardial infarction.
  • The procedure can be performed in real time during surgical interventions.
  • It is compatible with established therapies, as it does not necessarily interfere with other strategies such as cell therapy, mechanical circulatory support, or pharmacological treatments.

Nonetheless, important limitations remain, underscoring the need for further research:

• The isolation process is time-sensitive, and functional mitochondria can only be obtained under strict procedural conditions.
  • Current studies show wide variability in the dose and number of mitochondria used, emphasizing the need for standardized dosing and quantification methods.
  • A major drawback is the inability to store isolated mitochondria. Once harvested, they must be transplanted promptly to maintain function. Freezing or prolonged storage (>5 hours) induces structural changes that render them ineffective.
  • Another unresolved issue is whether exogenous mitochondria integrate durably into the endogenous mitochondrial network. It remains unclear whether they act as autonomous functional units or exert only transient effects through signal or metabolite transfer.

Taken together, mitochondrial transplantation, though still in early development, has opened a new avenue in regenerative medicine: targeted subcellular manipulation to restore energy homeostasis. While its implications extend beyond cardiovascular disease, it is in myocardial tissue—highly dependent on oxidative phosphorylation yet with limited regenerative capacity—where it may ultimately achieve its greatest clinical impact.

COMMENTARY:

Mitochondrial transplantation is reshaping the concept of therapeutic intervention by directly targeting the cell’s energy machinery. The strategy appears particularly promising in ischemic heart disease, where mitochondrial dysfunction plays a pivotal role in cell death and adverse remodeling. Despite the encouraging preclinical and early clinical results, several critical questions must be resolved before its widespread adoption. These include defining standardized protocols for mitochondrial isolation and delivery, clarifying mechanisms of integration and persistence within host tissue, and addressing logistical barriers to immediate-use transplantation. The success of ongoing clinical trials will determine whether this innovative approach can move from experimental therapy to a reproducible, safe, and effective clinical practice.

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