Bioenergetics Consequences of Mitochondrial Transplantation in Cardiomyocytes

Abstract

Background Mitochondrial transplantation has been recently explored for treatment of very ill cardiac patients. However, little is known about the intracellular consequences of mitochondrial transplantation. This study aims to assess the bioenergetics consequences of mitochondrial transplantation into normal cardiomyocytes in the short and long term. Methods and Results We first established the feasibility of autologous, non‐autologous, and interspecies mitochondrial transplantation. Then we quantitated the bioenergetics consequences of non‐autologous mitochondrial transplantation into cardiomyocytes up to 28 days using a Seahorse Extracellular Flux Analyzer. Compared with the control, we observed a statistically significant improvement in basal respiration and ATP production 2‐day post‐transplantation, accompanied by an increase in maximal respiration and spare respiratory capacity, although not statistically significantly. However, these initial improvements were short‐lived and the bioenergetics advantages return to the baseline level in subsequent time points. Conclusions This study, for the first time, shows that transplantation of non‐autologous mitochondria from healthy skeletal muscle cells into normal cardiomyocytes leads to short‐term improvement of bioenergetics indicating “supercharged” state. However, over time these improved effects disappear, which suggests transplantation of mitochondria may have a potential application in settings where there is an acute stress.

Stable retention of chloramphenicol-resistant mtDNA to rescue metabolically impaired cells

“…Mitochondrial function did improve in these dysfunctional cells after delivery, but the study was limited to four days in duration and the approach was unable to replace the endogenous detrimental mtDNA population. Another longer-term, four week study co-incubating mitochondria with WT cardiomyocytes reported only a temporary increase in mitochondrial function which, after two days, returned to the pre-transfer level of reduced respiration 28 . We observed that two weeks after transferring WT mitochondria into MELAS cells, whose respiration is similar to that of a ρ0 cell ( Supplementary Fig.…”

“…MitoPunch transfer of mitochondria into ρ0 cells. To begin, we used MitoPunch to transfer isolated mitochondria into ρ0 cells, to evaluate the reacquisition of respiratory function or to generate a model of mtDNA disease in a cell system that prior studies indicated should work [24][25][26][27][28]31,35 . ρ0 cells lack a functional electron transport chain (ETC), which blocks dihydroorotate dehydrogenase enzymatic activity and stops endogenous pyrimidine biosynthesis, leading to cell death with time 33,36,37 .…”

Mitochondrial transplantation—a possible therapeutic for mitochondrial dysfunction?

“…In an ischaemic pig heart model, prelabelled mitochondria were found up to 4 weeks after injection, although the authors did not analyse their functionality (Kaza et al , ). More recent bioenergetic studies on isolated mitochondria transferred into cardiomyocytes reported beneficial consequences on OXPHOS 2 days postinjection (Ali Pour et al , ), but this positive effect was not maintained. The same study noted a similar benefit with non‐autologous and even with interspecies transfer.…”

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

“…Overall, and similar to what is observed in the rescue of damaged cells following intercellular mitochondria transfer from MSCs, studies testing the therapeutic efficacy of mitochondria transplantation indicate that mitochondria need to be functional to exert their beneficial effects [ 178 , 182 , 188 ]. Strikingly, mitochondria used for therapeutic purposes may be of autologous, allogeneic, or xenogeneic origin, because, in all the cases, transplanted mitochondria have been reported to be non-immunogenic [ 178 , 185 , 186 , 187 , 188 , 189 , 190 ]. Although the mitochondrial transplantation procedure remains largely experimental, this technique has been successfully applied in the damaged hearts of five pediatric patients sharing ischemia-reperfusion-associated myocardial dysfunction [ 191 ].…”