Defect in Complex III of the Mitochondrial Electron Transfer System Affects Cardiac Insulin Sensitivity but Not Contractile Function

Objectives: Proper function of the mitochondrial electron transfer system (ETS) is a key factor for cardiac ATP production and consequently its contractile function. Indeed, a defect in Complex III of ETS has previously been associated with contractile dysfunction. Here, we assessed the impact of global respiratory Complex III deficiency based on UQCRH-KO mouse model generated at the German Mouse Clinic on cardiac mitochondrial ETS function and contractility.

Methods: Mitochondrial oxygen consumption, hydrogen peroxide production and the redox state of the quinone pool were studied in isolated heart mitochondria from wild-type (WT, n = 4) and UQCRH-KO (n = 4) mice using a NextGen-O2k (Oroboros Instruments, supported by EU H2020 research and innovation program, grant ID 859770). Cardiac contractile function and substrate oxidation rates were studied using the isolated working mouse heart model ex vivo (WT, n = 6; UQCRH-KO, n ≥ 3).

Result: In UQCRH-KO mitochondrial oxygen consumption was decreased (WT versus UQCRH-KO: 19.8 ± 4.7 vs. 9.4 ± 1.8 nmol/s/mg) and the reduction state of the quinone pool (redox ratio WT versus UQCRH-KO: 0.43 ± 0.05 vs. 0.78 ± 0.05) was increased while hydrogen peroxide production was largely unaffected. Interestingly, UQCRH-KO hearts presented a decreased heart rate (377 ± 27.8 vs. 274 ± 64.2 bpm) and an increased contractile function indicated by increased cardiac power (48.1 ± 10.7 vs. 97.4 ± 29.0 mW/g dry). Basal cardiac glucose and fatty acid oxidation were similar in WT and UQCRH-KO animals. However, insulin-induced stimulation of cardiac glucose oxidation (WT +2.02 ± 0.66 vs. UQCRH-KO +0.42 ± 0.33 µmol/min/g dry) and reduction in fatty acid oxidation (WT −0.40 ± 0.12 vs. UQCRH-KO −0.01 ± 0.48 µmol/min/g dry) were both blunted in UQCRH-KO hearts.

Conclusion: Our results in isolated mitochondria and the ex vivo working heart model suggest that Complex III defect alone does not necessarily trigger the development of a clinically relevant contractile dysfunction.

Publication History

Article published online:
19 February 2021