Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion

Abstract

Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI). The mitochondrial uncoupling protein 3 (UCP3) is down-regulated in the heart with insulin resistance. We hypothesized that decreased UCP3 levels contribute to poor cardiac recovery following ischemia/reperfusion (I/R). After confirming that myocardial UCP3 levels were systematically decreased by 20–49% in animal models of insulin resistance and type 2 diabetes, we genetically engineered Sprague–Dawley rats with partial loss of UCP3 (ucp3+/−). Wild-type littermates (ucp3+/+) were used as controls. Isolated working hearts from ucp3+/− rats were characterized by impaired recovery of cardiac power and decreased long-chain fatty acid (LCFA) oxidation following I/R. Mitochondria isolated from ucp3+/− hearts subjected to I/R in vivo displayed increased reactive oxygen species (ROS) generation and decreased respiratory complex I activity. Supplying ucp3+/− cardiac mitochondria with the medium-chain fatty acid (MCFA) octanoate slowed electron transport through the respiratory chain and reduced ROS generation. This was accompanied by improvement of cardiac LCFA oxidation and recovery of contractile function post ischemia. In conclusion, we demonstrated that normal cardiac UCP3 levels are essential to recovery of LCFA oxidation, mitochondrial respiratory capacity, and contractile function following I/R. These results reveal a potential mechanism for the poor prognosis of type 2 diabetic patients following MI and expose MCFA supplementation as a feasible metabolic intervention to improve recovery of these patients at reperfusion.Electronic supplementary materialThe online version of this article (10.1007/s00395-018-0707-9) contains supplementary material, which is available to authorized users.

Altered mitochondrial metabolism in the insulin‐resistant heart

“…There does not seem to be a role for UCP3 as a mechanism to transport FA out of the mitochondria during elevated FA supply, as has been suggested previously . However, enhanced UCP3 expression has been associated with the mitigation of oxidative stress, and in line with this there is evidence to suggest a relationship between increased mitochondrial ROS and UCP3 deficiency . In intact cell systems, mild mitochondrial uncoupling, due to a decrease in ∆Ψm, has been proposed to be a protective strategy under conditions of oxidative stress such as diabetes and obesity .…”

“…55 However, enhanced UCP3 expression has been associated with the mitigation of oxidative stress, 56 and in line with this there is evidence to suggest a relationship between increased mitochondrial ROS and UCP3 deficiency. 52,57,58 In intact cell systems, mild mitochondrial uncoupling, due to a decrease in ∆Ψm, has been proposed to be a protective strategy under conditions of oxidative stress such as diabetes and obesity. 50,59 However, this situation may only apply at the extremes of high redox potential, which is further elaborated within the R-ORB hypothesis (Redox-Optimized ROS Balance).…”

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…In the present study, 30 minutes of hypoxia and 4 hours of reoxygenation were used to induce cell damage. To suppress the AMPK pathway, compound C (CC; Selleck Chemicals) was added into the cell culture medium for two hours …”

“…To suppress the AMPK pathway, compound C (CC; Selleck Chemicals) was added into the cell culture medium for two hours. 33,34…”

Peer Review #2 of "Comprehensive analysis of long non-coding RNAs and mRNAs in skeletal muscle of diabetic Goto-Kakizaki rats during the early stage of type 2 diabetes (v0.1)"

“…Manuscript to be reviewed muscle (Bezaire et al 2005). The significantly decreased rate of long-chain fatty acid oxidation was observed in rat heart with partial loss of Ucp3 gene (Ucp3 +/− ) (Edwards et al 2018). Hence, in our study, the significantly increased Pdk4, and Ucp3 and their corresponding co-expressed or targeted lncRNAs, including NONRATG017315.2-Pdk4, and MSTRG.1662-Ucp3 might contribute to increased glycaemia and increased fatty acid oxidation in GK rats at 3 and 4 weeks of age.…”