Transit and integration of extracellular mitochondria in human heart cells

Abstract

Tissue ischemia adversely affects the function of mitochondria, which results in impairment of oxidative phosphorylation and compromised recovery of the affected organ. The impact of ischemia on mitochondrial function has been most extensively studied in the heart because of the morbidity and mortality associated with injury to this organ. Because conventional methods to preserve cell viability and function following an ischemic injury are limited in their efficacy, we developed a unique approach to protect the heart by transplanting respiration-competent mitochondria isolated from a non-ischemic tissue to the ischemic region. Our experiments in animals have shown that transplantation of isolated mitochondria to injured heart tissue leads to decreases in cell death, increases in energy production, and improvements in contractile function. We also discovered that exogenously-derived mitochondria injected or perfused into ischemic hearts were readily internalized by cardiac cells through actin-dependent endocytosis. Here, we describe the use of three-dimensional super-resolution microscopy and transmission electron microscopy to determine the intracellular fate of exogenous mitochondria in non-dividing human iPS-derived cardiomyocytes and dividing primary human cardiac fibroblasts. We show isolated mitochondria are internalised in human cardiac cells within minutes and then transported to endosomes and lysosomes. The majority of exogenous mitochondria escape from these compartments and fuse with the endogenous mitochondrial network, while some organelles are degraded through hydrolysis. Understanding this process may guide the development of treatments directed at replacing or augmenting impaired mitochondria in ischemic tissues and provide new options to rejuvenate dysfunctional mitochondria in a wide range of human diseases and disorders.

Mitochondrial transplantation therapy inhibit carbon tetrachloride‐induced liver injury through scavenging free radicals and protecting hepatocytes

“…Majority of them escape from the lysosomes and play roles in cytosol. 22 Then the mitochondria exhibit the ability to increase ATP production, activate the anti‐oxidative system and reduce the ROS level, which leads to cell viability increase and functional recovery in a certain concentration range 23,24 . Recent reports also suggest that mitochondrial transplantation therapy can lead to enhanced bioenergetics in normal cardiomyocytes, and meanwhile there is no increase in superoxide production 25 .…”

Commentary: Mitochondria are more than just the cells' powerhouse

“…The authors have previously documented uptake after vascular delivery in small animal ex vivo models, 3 and have also identified mechanisms of uptake by endocytosis, as well as intracellular trafficking to the native mitochondrial network in cell models. 4 However, the 5-to 10-minute time frame referenced in the current article's discussion section might be inconsistent with a more rapid coronary transit time. Reporting the intramyocardial mitochondrial population and uptake efficiency in the present study would have been helpful in supporting internalization with intravascular delivery.…”

Mitochondrial Transfer through Pericardium Contributes to Functional Recovery in Ischemic Cardiomyopathy

“…Additionally, evaluation of the direct myocardial transplantation of isolated mitochondria suggest a mechanism whereby cardiomyocytes directly internalize mitochondria through the cell membrane. These processes are considered to be non-speci c and re ect passive transfer [40][41][42][43]. Herein, mitochondrial transfer was promoted by hypoxic stimulation in vitro, and mitochondrial transfer from the myocardium to hADSCs was prevented by a connexin blocker in vivo.…”