Phospholipids, particularly cardiolipin (CL) and phosphatidic acid (PA) are known as critical regulators of mitochondrial membrane architecture and dynamics. Endoplasmic reticulum (ER) is the major site of phospholipid biosynthesis for mitochondria; ER-mitochondria contact sites or so-called Mitochondria-ER Associated Membranes (MAMs) serve as the platforms for phospholipid exchange between ER and mitochondria. MAM dysfunction disturbs phospholipid metabolism, thereby disrupting mitochondrial architecture and function. As such, maintaining metabolic homeostasis of phospholipids at MAMs is essential for the normal architecture and functioning of mitochondria. However, we have little or no knowledge on how phospholipid biosynthesis and exchange at the MAMs is regulated in adipocytes and what factors are involved in these regulatory processes. We have been characterizing the metabolic role of lipocalin 2 (Lcn2) as a critical regulator of thermogenic adipocyte activation and mitochondrial respiration. Lcn2 KO mice exhibit impaired thermogenesis as well as exacerbated diet-induced obesity and insulin resistance. Notably, deletion of Lcn2 disrupts mitochondrial architecture, dysregulates mitochondrial dynamics, and impairs mitochondrial respiration in brown and beige adipocytes, whereas overexpression of Lcn2 in adipose tissue promotes thermogenesis, increases mitochondrial metabolism of brown adipose tissue, and activates beiging of white adipose tissue without thermogenic stimulation. Most intriguingly, we discovered that Lcn2 is localized at MAMs in adipocytes, and Lcn2 has ability to strongly and selectively bind phosphatidic acid (PA). We hypothesize that Lcn2 plays a key role as a novel PA binding protein in the regulation of PA transport through MAM providing the precursor for CL biosynthesis, thereby maintaining mitochondrial phospholipid homeostasis and health. We proposed three Aims to 1) characterize the role of Lcn2 in PA transport, 2) determine the role of Lcn2 in CL biosynthesis, and 3) determine the role of Lcn2 in MAM function and mitochondrial dynamics in thermogenic adipocytes. We believe that this project will open a novel avenue to understand the molecular mechanisms for the dysregulation of mitochondrial bioenergetics in thermogenic adipocytes in obesity and during aging.
We have little or no knowledge on how disruption of phospholipid metabolism contributes mitochondrial dysfunction in adipocytes. This grant proposes studies to identify the novel role of Lipocalin 2 in mitochondrial bioenergetics through regulating phospholipid metabolism in thermogenic adipocytes. This project will open a novel avenue to understand the molecular mechanisms for the dysregulation of mitochondrial bioenergetics in thermogenic adipocytes in obesity and during aging.