Mitochondria as mediators of ischemia-reperfusion injury in rats with high or low intrinsic exercise capacity
Final Report Abstract
Cardiac ischemic events or long ischemic times during transportation of donor hearts are situations leading to cardiac damage and increase morbidity and mortality. Several mechanisms have been proposed, which highlight mitochondria as important regulators of cardiac damage or contractile recovery following ischemia-reperfusion (IR). The severity of IR damage in the heart is affected by factors such as duration of ischemia, comorbidities but most importantly the individual`s exercise capacity. In a model of rats with genetically determined high (HCR) or low (LCR) exercise capacity, we have shown that LCR presented with higher cardiac contractile recovery following IR and hypothesized that the differences in cardiac mitochondria may be responsible for this effect. The aim of the current project was to investigate the role of mitochondria in the recovery of the heart after ischemiareperfusion in a conplastic rat model of HCR and LCR, where mitochondria have been exchanged between the original HCR and LCR. Interestingly, exercise capacity and glucose tolerance increased in HCR and in LCR with exchanged mitochondria compared to their respective controls (HCR and LCR with their original mitochondria). Unexpectedly, mitochondrial exchange resulted in an improved cardiac contractile recovery following IR in both, HCR and LCR. This was accompanied by lower fatty acid oxidation rates during reperfusion in HCR with LCR mitochondria compared to HCR with their original mitochondria. The same effect was observed in LCR with exchanged mitochondria, suggesting higher cardiac efficiency. These data support the notion, that mitochondrial DNA differences affect cardiac IR recovery and substrate metabolism in rats with high and low intrinsic exercise capacity. This further suggests an important interplay between mitochondrial and nuclear DNA and highlights mitochondria as important target for therapeutic strategies.
Publications
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Intrinsic Exercise Capacity Affects Glycine and Angiotensin-Converting Enzyme 2 (ACE2) Levels in Sedentary and Exercise Trained Rats. Metabolites, 12(6), 548.
Klöting, Nora; Schwarzer, Michael; Heyne, Estelle; Ceglarek, Uta; Hoffmann, Anne; Krohn, Knut; Doenst, Torsten & Blüher, Matthias
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Knockout of the Complex III subunit Uqcrh causes bioenergetic impairment and cardiac contractile dysfunction. Mammalian Genome, 34(2), 229-243.
Spielmann, Nadine; Schenkl, Christina; Komlódi, Tímea; da Silva-Buttkus, Patricia; Heyne, Estelle; Rohde, Jana; Amarie, Oana V.; Rathkolb, Birgit; Gnaiger, Erich; Doenst, Torsten; Fuchs, Helmut; Gailus-Durner, Valérie; de Angelis, Martin Hrabě & Szibor, Marten
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Measuring the Mitochondrial Ubiquinone (Q) Pool Redox State in Isolated Respiring Mitochondria. Methods in Molecular Biology, 291-299. Springer US.
Szibor, Marten; Heyne, Estelle; Viscomi, Carlo & Moore, Anthony L.
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The IGF-1R Inhibitor NVP-AEW541 Causes Insulin-Independent and Reversible Cardiac Contractile Dysfunction. Biomedicines, 10(8), 2022.
Schenkl, Christina; Schrepper, Andrea; Heyne, Estelle; Doenst, Torsten & Schwarzer, Michael
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Impact of mitochondrial switching on contractile performance and substrate oxidation in the isolated working heart in rats with high or low genetically determined exercise capacity. 2023 Annual meeting of Deutsche Gesellschaft für Kardiologie
Heyne E., Reimann G., Hoffmann J., Mell B., Joe B., Doenst T. & Schwarzer M.
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Mitochondrial DNA differences in rats with high or low genetically determined exercise capacity affect cardiac function and metabolism. 2023 Annual meeting of the Society for Heart and Vascular Metabolism
Heyne E., Reimann G., Hoffmann J., Preuß K., Mell B., Joe B., Doenst T. & Schwarzer M.
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Targeting Mitochondrial Metabolism to Save the Failing Heart. Life, 13(4), 1027.
Schenkl, Christina; Heyne, Estelle; Doenst, Torsten; Schulze, Paul Christian & Nguyen, Tien Dung
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Exercise Training Differentially Affects Skeletal Muscle Mitochondria in Rats with Inherited High or Low Exercise Capacity. Cells, 13(5), 393.
Heyne, Estelle; Zeeb, Susanne; Junker, Celina; Petzinna, Andreas; Schrepper, Andrea; Doenst, Torsten; Koch, Lauren G.; Britton, Steven L. & Schwarzer, Michael
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Hyperbaric oxygen treatment reveals spatiotemporal OXPHOS plasticity in the porcine heart. PNAS Nexus, 3(6).
Heidler, Juliana; Cabrera-Orefice, Alfredo; Wittig, Ilka; Heyne, Estelle; Tomczak, Jan-Niklas; Petersen, Bjoern; Henze, Dirk; Pohjoismäki, Jaakko L. O. & Szibor, Marten
