Higher Cardiac Ischemia and Reperfusion Tolerance in Complex III–deficient (Uqcrh-KO) Mice Is Associated with a Shift from Oxidative to Anaerobic Metabolism

Background: The mitochondrial electron transport chain (ETC) is the central building block for oxidative metabolism and ATP production, and thus stalling of electron flux through the ETC commonly compromises cardiac contractile function. Recently, we generated a knockout mouse model of the Uqcrh gene (Uqcrh-KO), which is essential for electron transfer between cytochrome c1 and c of the mitochondrial cytochrome bc1 complex (cIII). Uqcrh-KO mice present with impaired cIII maturation and catalytic function, marked developmental delay, global metabolic abnormalities such as hyperglycemia, and premature death. Here we set out to test how Uqcrh-KO affects cardiac contractile function and substrate use in the unstressed and postischemic heart.

Method: Hearts from 12-week-old Uqcrh-KO mice and wild-type littermates were characterized in vivo and ex vivo using echocardiography and the isolated working mouse heart. We assessed cardiac contractile function and substrate oxidation rates in response to insulin stimulation as well as before ischemia and during reperfusion.

Results: Uqcrh-KO mice and hearts were smaller compared with wild-type, while heart weight to body weight appeared normal. Echocardiographic analysis revealed that Uqcrh-KO mice have a lower heart rate compared with wild-type but no further morphological abnormalities. In the isolated working heart cardiac power was higher in Uqcrh-KO compared with wild-type when related to heart weight. Under normoxic conditions, Uqcrh-KO hearts showed a strong shift to anaerobic metabolism with higher glucose uptake, glycolysis and lactate release compared with wild-type. Besides that, there was no effect of insulin stimulation on fatty acid and glucose oxidation. Performing a normothermic no-flow ischemia revealed, that 83% of wild-type hearts recovered functionally with an average loss of 35% cardiac power compared with pre-ischemia. This lack of recovery in wild-type hearts was associated with increased glucose oxidation and lactate release during reperfusion. However, all hearts of Uqcrh-KO fully recovered after ischemia with no changes in substrate usage and cardiac power, which was comparable to preischemic state.

Conclusion: Our results indicate that Uqcrh-KO-mediated cIII impairment shifts cardiac metabolism from oxidative to anaerobic and is associated with a higher ischemia and reperfusion tolerance.

Publikationsverlauf

Artikel online veröffentlicht:
28. Januar 2023