Stem Cell‐Derived Mitochondria‐Enriched Preservation Solutions as Organelle‐Based Therapeutic Strategy for Cold Storage of Liver and Kidney

ABSTRACT

Organ preservation remains a critical challenge in transplantation, primarily due to hypothermia‐induced oxidative stress and metabolic dysfunction. Here, we report a mitochondria‐enriched, cell‐free preservation strategy by supplementing standard preservation solutions with freshly isolated mitochondria derived from human induced pluripotent stem cell–mesenchymal stem cells (MSC‐mt). MSC‐mt retained intact ultrastructure and functional biophysical properties. In vitro, MSC‐mt were internalized by hepatocyte‐ and kidney‐derived cells, reduced oxidative stress, preserved ATP levels, and attenuated apoptosis under cold stress. Ex vivo , MSC‐mt improved liver preservation in University of Wisconsin (UW) solution, reducing sinusoidal edema, apoptosis, ALT/AST release, MDA accumulation, and oxidative DNA damage while enhancing SOD activity and preserving mitochondrial content. Human‐specific mitochondrial signals remained detectable within preserved hepatic tissue. In a warm reoxygenation model, MSC‐mt enhanced ATP recovery and reduced tissue injury and oxidative damage following cold storage. In kidneys, MSC‐mt provided stronger protection than fibroblast‐ or adipose‐derived mitochondria across both HC‐A and UW solutions. Mechanistically, MSC‐mt showed higher total and phosphorylated PINK1 levels and greater Parkin co‐localization than fibroblast‐derived mitochondria, while mitophagy inhibition partially reversed their antioxidant effects. These findings establish MSC‐mt as a cell‐free mitochondrial strategy for improving hypothermic organ preservation.