Mitochondrial transplantation for myocardial protection in diabetic hearts

Abstract

OBJECTIVES Type 2 diabetes causes mitochondrial dysfunction, which increases myocardial susceptibility to ischaemia–reperfusion injury. We investigated the efficacy of transplantation of mitochondria isolated from diabetic or non-diabetic donors in providing cardioprotection from warm global ischaemia and reperfusion in the diabetic rat heart. METHODS Ex vivo perfused hearts from Zucker diabetic fatty (ZDF fa/fa) rats (n = 6 per group) were subjected to 30 min of warm global ischaemia and 120 min reperfusion. Immediately prior to reperfusion, vehicle alone (VEH) or vehicle containing mitochondria isolated from either ZDF (MTZDF) or non-diabetic Zucker lean (ZL +/?) (MTZL) skeletal muscle were delivered to the coronary arteries via the aortic cannula. RESULTS Following 30-min global ischaemia and 120-min reperfusion, left ventricular developed pressure was significantly increased in MTZDF and MTZL groups compared to VEH group (MTZDF: 92.8 ± 5.2 mmHg vs MTZL: 110.7 ± 2.4 mmHg vs VEH: 44.3 ± 5.9 mmHg; P < 0.01 each); and left ventricular end-diastolic pressure was significantly decreased (MTZDF 12.1 ± 1.3 mmHg vs MTZL 8.6 ± 0.8 mmHg vs VEH: 18.6 ± 1.5 mmHg; P = 0.016 for MTZDF vs VEH and P < 0.01 for MTZL vs VEH). Total tissue ATP content was significantly increased in both MT groups compared to VEH group (MTZDF: 18.9 ± 1.5 mmol/mg protein/mg tissue vs MTZL: 28.1 ± 2.3 mmol/mg protein/mg tissue vs VEH: 13.1 ± 0.5 mmol/mg protein/mg tissue; P = 0.018 for MTZDF vs VEH and P < 0.01 for MTZL vs VEH). Infarct size was significantly decreased in the MT groups (MTZDF: 11.8 ± 0.7% vs MTZL: 9.9 ± 0.5% vs VEH: 52.0 ± 1.4%; P < 0.01 each). CONCLUSIONS Mitochondrial transplantation significantly enhances post-ischaemic myocardial functional recovery and significantly decreases myocellular injury in the diabetic heart.

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

“…In particular, this therapeutic approach has been invariably shown to significantly reduce hypoxic/ischemic insult and restore tissue function following myocardial infarction [ 173 , 174 , 175 , 176 ], acute kidney injury [ 177 ], stroke [ 178 , 179 ], spinal cord injury [ 180 , 181 ], or optic nerve crush leading to glaucoma [ 182 ] by improving the bioenergetics and cell survival and by decreasing oxidative stress and mitochondrial DNA damages. Similarly, mitochondria transplantation has been reported to exert beneficial effects in animal models for either metabolic syndromes, including diabetic ischemic heart [ 183 ] and non-alcoholic fatty liver [ 184 ], or for neurological disorders, such as Parkinson’s disease [ 185 , 186 ] and schizophrenia [ 187 ]. Beyond mitochondrial disease treatment, the transplantation of exogenous mitochondrial has been evaluated in the attempt to mitigate mitochondrial dysfunction of cancer cells.…”

“Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

“…Although these studies produced positive results with regard to efficacy of mitochondrial transplantation, experiments using mitochondria from diseased patients, which would mirror more closely the real-life situation where this protocol would be applied, are rare. To our knowledge the first study mimicking the transplantation of mitochondria from diseased diabetic animals was conducted by Doulamis et al in 2020 [134]. In a Langendorff perfused rodent heart model they investigated the transplantation success using either autologous (diabetic) or syngeneic (non-diabetic) mitochondria generated from skeletal muscle tissue.…”

“…Using healthy non-autologous mitochondria might even be more beneficial than using autologous mitochondria. For example mitochondria in diabetic patients and rodent models have been shown to be dysfunctional, having reduced respiratory capacity and ATP production rate [134]. In addition, autologous mitochondria might not be an option in patients with mitochondrial myopathies and mutational changes in the mtDNA [167].…”

Challenges in Promoting Mitochondrial Transplantation Therapy

“…Left ventricular function recovery, reduction of IS/AAR Doulamis et al, 2020 [10] Pediatric patients with ischemia-reperfusion associated myocardial function…”

“…In a rat model of diabetes, the therapeutic effect of mitochondrial transplantation was investigated by administering isolated mitochondria to the heart [ 10 ]. When the rat heart was subjected to warm global ischemia, autologous or allogeneic mitochondria isolated from the pectoralis major muscle was administered via the coronary artery.…”