Selective integration of transplanted mitochondria drive sustained metabolic and functional rescue in MELAS endothelial cells through enhanced protein translation

Abstract Mitochondrial diseases such as mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) manifest due to mutations in the mitochondrial genome. This leads to defects in mitochondrial respiration and ATP generation, affecting normal cellular function. Recently, it has been shown that the transfer of healthy donor mitochondria into recipient cells, termed “mitotherapy”, has been successful in boosting recipient cell metabolism and function. However, the mechanistic route by which mitotherapy promotes cellular function is uncertain. Here we demonstrate in vitro uptake of exogenous donor mitochondria and expression of the donor mitochondrial genes, resulting in metabolic and functional improvements in MELAS endothelial cells. Improvements were evident at both early and prolonged time points following treatment using healthy, functioning mitochondria, in contrast to the treatment of MELAS mutant mitochondria or sonicated healthy mitochondria. Transcriptomic analysis suggests that the improved cellular energetics enabled an upregulation of translation machinery, potentially counteracting the translational deficiencies characteristic of MELAS. Importantly, the treated healthy wild-type mitochondria are retained in recipient MELAS endothelial cells, decreasing their mutant mitochondrial DNA load, termed heteroplasmy. These findings suggest a novel route in tackling diseases that stem from mitochondrial dysfunctions.