Impaired mitochondrial bioenergetics in brown adipocytes links to the disrupted energy metabolism and thermogenesis in obesity. Phospholipids, particularly cardiolipin and phosphatidic acid (PA) are critical regulators of mitochondrial membrane architecture and dynamics. Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as the platform for phospholipid biosynthesis. MAM dysfunction disturbs phospholipid metabolism, thereby disrupting mitochondrial function. However, little is known about the participating factors that regulate MAM phospholipid metabolism. We have previously characterized the role of lipocalin 2 (Lcn2) in thermogenesis and mitochondrial function in adipocytes. Herein, we found that Lcn2 was located at MAMs and had a specific PA binding capability. The mitochondrial fusion-fission process induced by the fasting-refeeding cycle was impaired in Lcn2 knockout (KO) brown adipocytes. We also observed that the levels of phosphorylated Drp1 (Ser616) and Opa1 were decreased in brown adipose tissue (BAT) of Lcn2 KO mice compared to WT controls upon acute cold stimulation, whereas Lcn2 overexpression in BAT led to an increase in Drp1 phosphorylation and Opa1 level. Moreover, Lcn2 deficiency significantly enhanced the cold-stimulated accumulation of Opa1 as well as MAM markers SigmaR1, Ip3R1, and Facl4 at MAMs in BAT, suggesting impaired MAM function. CL316,243, a β3-adrenergic receptor agonist has a cold mimic effect on mitochondrial bioenergetics. In brown adipocytes, Lcn2 deficiency significantly attenuated the CL316,243 induction of Drp1 phosphorylation. Intriguingly, lipidomic analysis of BAT mitochondria isolated from mice treated with CL316,243 for 14 days showed that Lcn2 deficiency blunted CL316,243-induced cardiolipin biosynthesis and altered phospholipid metabolism. Together, we discovered a role of Lcn2 as a novel PA transfer protein in mitochondrial bioenergetics via regulating phospholipid metabolism.


H.Su: None. H.Guo: None. X.Qiu: None. T.Lin: None. X.Chen: None.


This work was supported by NIDDK Grant (RDK123042) awarded to Xiaoli Chen.

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