Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

UQCRH-KO mediated complex III defect modulates cardiac energy metabolism associated with enhanced ischemia tolerance
G. Reimann1, R. Gerlini2, N. Spielmann2, V. Gailus-Durner2, M. Hrabě de Angelis2, T. Doenst1, M. Schwarzer1
1Klinik für Herz- und Thoraxchirurgie, Universitätsklinikum Jena, Jena; 2Institute of Experimental Genetics, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg;

Background Cardiac function is related to substrate oxidation, which is mainly located in mitochondria. While being the main producer of ATP, mitochondrial function directly affects contractile function. Mitochondria are equally important for the flexibility in substrate oxidation, which is highly relevant in cardiac stress such as ischemia/reperfusion. A defect in complex III of the mitochondrial respiratory chain has been found in two male patients and has been reproduced in mice as a UQCRH knockout (UQCRH-KO). Under physiological conditions, UQCRH mediates the electron transport between complex III and cytochrome c in the mitochondrial electron transfer system and is therefore elementary for its function. Defects in complex III activity have previously been associated with contractile dysfunction. We hypothesized an impact of the global respiratory complex III deficiency based on the UQCRH-KO mice on cardiac function and energy metabolism. Thus, we aimed to characterize UQCRH-KO mouse heart substrate oxidation, basal and in response to insulin application as well as ischemia-reperfusion outcome as an acute stress model.

Method Cardiac contractile function and substrate oxidation rates were studied in UQCRH-KO and wild type mice at the age of 12 weeks using the ex vivo isolated working mouse heart (n = 9‑11 for each experimental group). Radiolabeled tracers were used to measure fatty acid oxidation (oleate), glucose oxidation and glycolysis. Hearts were allowed to beat spontaneously. After 45 min of basal perfusion, hearts were stimulated with 0.5 mU/ml insulin to reach maximal insulin response for further 45 min of working heart. In a second experimental group, after 40 min of basal perfusion, UQRCH-KO and wild type hearts were exposed to global, normothermic, no-flow ischemia followed by additional 40 min of reperfusion.

Results Hearts of the UQCRH-KO mice were smaller compared to wild type littermates (WT: 118.6 ± 13.5; UQCRH-KO: 56.2 ± 5.9 mg) but comparable when related to body weight (WT: 5.2 ± 0.2; UQCRH-KO: 5.1 ± 1.0 g/kg). UQCRH-KO hearts presented with decreased heart rate (WT: 347 ± 24; UQCRH-KO: 230 ± 35 bpm) but increased cardiac power normalized to heart dry weight. Basal cardiac glucose and fatty acid oxidation rates (normalized to dry weight) were comparable in UQCRH-KO and wild type hearts. In contrast, the ratio of glycolysis to glucose-oxidation increased due to increased glycolysis (WT: 5.8 ± 1.8; UQCRH-KO: 14.3 ± 2.9). Lactate production increased as well in UQCRH‑KO hearts (WT: 10.4 ± 5.8; UQCRH-KO: 27.2 ± 10.5 nmol/min/mgdry). Additionally insulin-stimulation led to increased glucose oxidation, glycolysis and lactate production as well as decreased fatty acid oxidation in wild type hearts. However, all these insulin effects were blunted in UQCRH-KO hearts. When exposed to ischemia UQCRH‑KO hearts showed an increased amount of hearts recovering from ischemia (WT: 81.8%, 9/11; UQCRH‑KO: 100%, 9/9) and performed with higher post ischemic cardiac power in comparison to wild type (WT: 66.0 ± 9.2; UQCRH‑KO: 87.4 ± 14.8 reperfusion cardiac power/% baseline).

Conclusion Our results suggest that the UQCRH-KO mediated complex III defect caused a shift from oxidative to anaerobic metabolism in combination with altered cardiac insulin response. Those metabolic changes were associated with an enhanced ischemia tolerance in UQCRH-KO hearts.


https://dgk.org/kongress_programme/jt2022/aP1981.html