Mitochondrial phosphatidylethanolamine modulates UCP1 to promote brown adipose thermogenesis

Abstract

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist–induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PE-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.

Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling

“…2F-H). The modulation of phospholipid genes was interesting considering a recent study that linked phosphatidylethanolamine (PE), a main phospholipid of mitochondrial membranes, with regulation of proton conductance by the uncoupling protein 1 (UCP1), at least in brown adipose tissue 20 . Uncoupling through proton dissipation is a known mechanism to regulate the ΔΨM.…”

“…That a chronic rise in the ΔΨM leads to phospholipid remodeling is clear based on our data, but why such remodeling occurs remains to be fully defined. In brown adipose tissue, PE in the mitochondrial membrane was recently shown to regulate proton flux through UCP1, presumably affecting the ΔΨM although this was not measured 20 . While our cells do not express UCP1, we speculate that an increase in the PE content in the mitochondria membrane of IF1-KO cells could be deployed in a similar fashion to allow maintaining an optimal hyperpolarized state supporting proper mitochondrial and/or cellular function.…”

IFI27 Integrates Succinate and Fatty Acid Oxidation to Promote Adipocyte Thermogenic Adaption

“…PC (34:2) is the most plentiful PC in BAT mitochondria at room temperature, and it is further increased after mice are housing at 6.5 °C for 7 days. [ 49 ] A reduction in mitochondrial PC or ether PE content is associated with abnormal mitochondrial function and morphogenesis. [ 27 , 50 ] Loss of Ifi27 has a considerable impact on the glycerolphospholipid composition in BAT, indicating IFI27 deficiency may alter phospholipid synthesis pathway in ER and peroxisome.…”

Post-translational modulation of cell signalling through protein succinylation

“…This cold intolerance was caused by a decrease in the browning capacity of their BAT, although an overall increase in adipose tissue compared to wild-type (WT) mice was noted [ 67 ]. The thermogenic capacity of adipocytes primarily relies on the activity of the UCP-1 which acts as a proton channel in the inner mitochondrial membrane and generates heat instead of ATP [ 68 ]. The thermogenic marker UCP-1 as well as the messenger RNA (mRNA) levels for proteins related to mitochondrial metabolism and biogenesis were markedly down-regulated in the adipose tissue of SIRT5 KO mice [ 58 ].…”