Korean J Physiol Pharmacol.  2024 May;28(3):209-217. 10.4196/kjpp.2024.28.3.209.

Cardioprotection via mitochondrial transplantation supports fatty acid metabolism in ischemia-reperfusion injured rat heart

• Jang J
• Kang KW
• Kim YW
• Jeong S
• Park J
• Park J
• Moon J
• Jang J
• Kim S
• Kim S
• Cho S
• Lee Y
• Kim HK
• Han J
• Ko EA
• Jung SC
• Kim JH
• Ko JH

• KMID: 2555663
• DOI: http://doi.org/10.4196/kjpp.2024.28.3.209

Abstract

In addition to cellular damage, ischemia-reperfusion (IR) injury induces substantial damage to the mitochondria and endoplasmic reticulum. In this study, we sought to determine whether impaired mitochondrial function owing to IR could be restored by transplanting mitochondria into the heart under ex vivo IR states. Additionally, we aimed to provide preliminary results to inform therapeutic options for ischemic heart disease (IHD). Healthy mitochondria isolated from autologous gluteus maximus muscle were transplanted into the hearts of Sprague–Dawley rats damaged by IR using the Langendorff system, and the heart rate and oxygen consumption capacity of the mitochondria were measured to confirm whether heart function was restored. In addition, relative expression levels were measured to identify the genes related to IR injury. Mitochondrial oxygen consumption capacity was found to be lower in the IR group than in the group that underwent mitochondrial transplantation after IR injury (p < 0.05), and the control group showed a tendency toward increased oxygen consumption capacity compared with the IR group. Among the genes related to fatty acid metabolism, Cpt1b (p < 0.05) and Fads1 (p < 0.01) showed significant expression in the following order: IR group, IR + transplantation group, and control group. These results suggest that mitochondrial transplantation protects the heart from IR damage and may be feasible as a therapeutic option for IHD.

Keyword

Autografts; Mitochondria; Myocardial ischemia; Myocardial reperfusion; Oxygen consumption; Transplantation

Figure

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  Fig. 1 Observation of non-ischemic area at endpoint of animal experiment. (A) Schematic illustration of experimental protocol. (B) Representative cardiac sections stained with 0.25% Evans blue. The upper panel shows control group cardiac section stained with 0.25% Evans blue. The middle panel shows IR group cardiac section stained with 0.25% Evans blue. The lower shows IR + transpl group cardiac section stained with 0.25% Evans blue. CON (control), group without ischemia or reperfusion injury; IR, group with damage induced by ischemia and reperfusion; IR + transpl, group transplanted with isolated mitochondria after inducing IR damage.

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  Fig. 2 Changes in heart rate over time by group. All isolated hearts showed normal ex vivo heart rates during the experiment. CON (control), group without ischemia or reperfusion injury; IR, group with damage induced by ischemia and reperfusion; IR + transpl, group transplanted with isolated mitochondria after inducing IR damage.

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  Fig. 3 Mitochondrial function analysis. (A) RCR tracked ATP production by assessing the oxygen consumption capacity of mitochondria. *p < 0.05 indicates that the group means are not all statistically equal. #p < 0.05 denoted a comparison between IR and IR + transpl. (B) mtDNA-DN assessed cellular ATP requirements. (C) Oxygen consumption per unit mitochondria was confirmed. CON (control), group without ischemia or reperfusion injury; IR, injury due to ischemia and reperfusion group; IR + transpl, group transplanted with isolated mitochondria after inducing IR injury; mtDNA-CN, mitochondrial DNA copy number; RCR, respiratory control ratio; ATP, adenosine triphosphate.

• 

  Fig. 4 Relative expression levels of target genes. Comparison of cardiac gene expression levels associated with fatty acid energy metabolism in the mitochondrial transplantation. Statistically significant results indicated that the group means are not equal, with significance levels of *p < 0.05 and **p < 0.01. The gene expression showed statistically significant differences, with #p < 0.05 and ##p < 0.01 indicating levels of significance. CON (control), group without ischemia or reperfusion injury; IR, group with damage induced by ischemia and reperfusion; IR + transpl, group transplanted with isolated mitochondria after inducing IR damage; Cpt1b, carnitine palmitoyltransferase 1B; Elovl5, ELOVL fatty acid elongase 5; Fads1, fatty acid desaturase 1; Gja1, gap function alpha 1.

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