Muscle mitochondrial transplantation can rescue and maintain cellular homeostasis

Abstract

Mitochondria control cellular functions through their metabolic role. Recent research that has gained considerable attention is their ability to transfer between cells. This has the potential of improving cellular functions in pathological or energy deficit conditions, but little is known about the role of mitochondrial transfer in sustaining cellular homeostasis. Few studies have investigated the potential of skeletal muscle as a source of healthy mitochondria that can be transferred to other cell types. Thus, we isolated intermyofibrillar mitochondria from murine skeletal muscle and incubated them with host cells. We observed dose- and time-dependent increases in mitochondrial incorporation into myoblasts. This resulted in elongated mitochondrial networks and an enhancement of bioenergetic profile of the host cells. Mitochondrial donation also rejuvenated the functional capacities of the myoblasts when respiration efficiency and lysosomal function were inhibited by complex I inhibitor rotenone and bafilomycin A, respectively. Mitochondrial transfer was accomplished via tunneling nanotubes, extracellular vesicles, gap junctions and by macropinocytosis internalization. Murine muscle mitochondria were also effectively transferred to human fibroblast cells having mitochondrial DNA mutations, resulting in augmented mitochondrial dynamics and metabolic functions. This improved cell function by diminishing ROS emission in the diseased cells. Our findings suggest that mitochondria from donor skeletal muscle can be integrated in both healthy and functionally compromised host cells leading to mitochondrial structural refinement and respiratory boost. This mitochondrial trafficking and bioenergetic reprogramming to maintain and revitalise tissue homeostasis could be a useful therapeutic strategy in treating diseases.

Mitochondrial Quantity and Quality in Age-Related Sarcopenia

“…The pivotal contribution of mitochondrial function and quality to muscle homeostasis and performance is also epitomized by increasing evidence showing that mitochondrial transplantation may be a therapeutic strategy for the bioenergetic reprogramming of diseased tissues, including the skeletal muscle [114][115][116].…”

“…Subsequently, clinical trials have been designed to evaluate the effectiveness of mitochondrial transplantation as a therapeutic strategy in various clinical conditions (NCT02586298, NCT02851758, NCT04998357, NCT04976140). More recent is the finding that transplanting intermyofibrillar mitochondria from murine skeletal myocytes to myoblasts improved myoblast bioenergetics [116]. Human fibroblasts harboring mtDNA mutations were also successfully transplanted with murine muscle mitochondria and showed improved mitochondrial dynamics, metabolism, and reduced levels of reactive oxygen species [116].…”

“…More recent is the finding that transplanting intermyofibrillar mitochondria from murine skeletal myocytes to myoblasts improved myoblast bioenergetics [116]. Human fibroblasts harboring mtDNA mutations were also successfully transplanted with murine muscle mitochondria and showed improved mitochondrial dynamics, metabolism, and reduced levels of reactive oxygen species [116]. The mitochondrial transfer occurred via extracellular vesicles, gap junctions, micropinocytosis, and tunneling nanotubes, thereby paving the way for less invasive techniques for organelle transplantation that exploit vesicle trafficking [116].…”

“…Human fibroblasts harboring mtDNA mutations were also successfully transplanted with murine muscle mitochondria and showed improved mitochondrial dynamics, metabolism, and reduced levels of reactive oxygen species [116]. The mitochondrial transfer occurred via extracellular vesicles, gap junctions, micropinocytosis, and tunneling nanotubes, thereby paving the way for less invasive techniques for organelle transplantation that exploit vesicle trafficking [116]. Finally, the incorporation of mitochondria into mesenchymal stem cells following organelle transplantation has been shown to improve the repair of arterial, lung, and cardiac tissue [122,123].…”

Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly

“…Therefore, devising minimally invasive approaches is highly sought after. Recently, the administration of intermyofibrillar mitochondria isolated from murine skeletal muscle to myoblasts resulted in time- and dose-dependent incorporation of mitochondria and organelle elongation, as well as improvement in myoblast bioenergetics [ 116 ]. The transfer of murine muscle mitochondria was also accomplished in human fibroblast bearing mtDNA mutations, with the effect of promoting mitochondrial dynamics and metabolism while reducing ROS levels [ 116 ].…”