Erythrocyte transglutaminase-2 combats hypoxia and chronic kidney disease by promoting oxygen delivery and carnitine homeostasis

Plasma Levels of Acyl-Carnitines and Carboxylic Acids Correlate With Cardiovascular and Kidney Function in Subjects With Sickle Cell Trait

“…Elevated oxidative stress in SCD targets the membrane lipid fraction, activating a pathway referred to as the Lands cycle for the tentative repair of damaged lipids through activation of phospholipase A2 enzymes to cleave oxidatively-damaged fatty acyl components, and transfer of acyl-moieties from CoA-conjugates (in equilibrium with acyl-carnitine pools) to lysophospholipids ( Wu et al, 2016 ). Of note, similar metabolic adaptations have been reported in RBCs in response to oxidative stress in chronic kidney disease ( Xu et al, 2022 ), acute kidney dysfunction ( Bissinger et al, 2021 ), COVID-19 ( Thomas et al, 2020a ) or in response to exercise-induced vesiculation ( Nemkov et al, 2021 ). Correction of these pathways—including fatty acid oxidation and acyl-carnitine metabolism ( Culp-Hill et al, 2018 ) - have been reported in SCD recipients upon exchange transfusion therapy.…”

“…For example, cardiovascular dysfunction in SCD has been at least in part explained as a function of free hemoglobin NO scavenging ( Gladwin et al, 2011 ; Drawz et al, 2016 ) or free heme/iron effect on immune cells as result of elevated intra- and extra-vascular hemolysis ( Buehler et al, 2021 ), respectively. In this view, it is interesting to note that extravascular hemolysis is favored by decreases in deformability, previously associated to alterations in acyl-carnitine, free fatty acids and oxylpin levels in the context of oxidant stress after exercise ( Nemkov et al, 2021 ), chronic ( Xie et al, 2020 ; Xu et al, 2022 ) or acute kidney ( Bissinger et al, 2021 ) dysfunction. While not as sever as previously reported in the context of SCD, here we noted significant increases in the plasma levels of acyl-carnitines and free fatty acids, suggestive of a potential increase in cell vesiculation events and a hallmark of the activation of the Lands cycle, a hallmark of membrane abnormalities in SCD ( Wu et al, 2016 ).…”

“…Small molecules like high-energy phosphate compounds, 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP) allosterically regulate hemoglobin by stabilizing the tense deoxygenated state ( Yuan et al, 2015 ) and promoting oxygen off-loading ( Donovan et al, 2021 ). Other signaling cascades at the metabolic level have been described in recent years as critical regulators of RBC physiological and pathological responses to hypoxia ( D'Alessandro and Xia, 2020 ), including (i) increases in the levels of plasma adenosine ( Liu et al, 2016 ), and (ii) sphingosine 1-phosphate ( Sun et al, 2016 ); (iii) stabilization of the enzyme bisphosphoglycerate mutase by post-translational modification via RBC transglutaminase 2 ( Xu et al, 2022 ); (iv) rewiring of RBC glucose oxidation from the pentose phosphate pathway (at high O 2 saturation) to glycolysis (at low O 2 saturation) as a strategy to boost the generation of ATP and DPG at the expense of the capacity to generate reducing equivalents to sustain antioxidant reactions (i.e., NADPH) ( Reisz et al, 2016 ; Issaian et al, 2021 ); (v) further stabilization of deoxyhemoglobin at the membrane through binding to the N-terminus cytosolic domain of band 3, the most abundant membrane protein in RBCs ( Lewis et al, 2009 ). All of these metabolic pathways are critical to RBC physiological responses to hypoxia, but are detrimental in the context of SCD, where stabilization of the deoxygenated form of HbS favors polymerization and sickling ( Zhang et al, 2011 ; Sun et al, 2015 ; Wu et al, 2016 ; Sun et al, 2017a ).…”

Reprogramming of red blood cell metabolism in Zika virus–infected donors

“…Alterations to the RBC lipidome are critical mediators of RBC deformability, 101 which in turn impacts their propensity for splenic sequestration and untimely removal from circulation upon transfusion 102 . Altered acyl‐carnitines profiles, such as those observed here in ZIKV IgM‐positive donors, have been previously reported in RBC with increased susceptibility to hemolyze following osmotic insults, such as those from donors undergoing testosterone replacement therapy 71 or in response to chronic kidney disease 57 or kidney dysfunction 103 . Indeed, acyl‐carnitine levels are indicative of the activation of the Lands cycle, a pathway that in mature RBCs is activated in response to stress to membrane lipids 58 …”

“…102 Altered acyl-carnitines profiles, such as those observed here in ZIKV IgM-positive donors, have been previously reported in RBC with increased susceptibility to hemolyze following osmotic insults, such as those from donors undergoing testosterone replacement therapy 71 or in response to chronic kidney disease 57 or kidney dysfunction. 103 Indeed, acylcarnitine levels are indicative of the activation of the Lands cycle, a pathway that in mature RBCs is activated in response to stress to membrane lipids. 58 The finding that RBC from healthy donors could still test positive up to months from the original infection is interesting in that RBCs could be serve as a reservoir for infection of permissive cells by participating in viral dissemination to tissues susceptible to ZIKV.…”