Mitochondrial Phosphatidylethanolamine Directly Regulates 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 ATP synthase. Here we provide evidence that mitochondrial phosphatidylethanolamine (PE) directly regulates UCP1-dependent proton conductance across 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 PSD-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.…”