Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice

Hongming Su, Hong Guo, Xiaoxue Qiu, Te-Yueh Lin, Chao Qin, Gail Celio, Peter Yong, Mark Senders, Xianlin Han, David A. Bernlohr and Xiaoli Chen ()
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Hongming Su: University of Minnesota-Twin Cities
Hong Guo: University of Minnesota-Twin Cities
Xiaoxue Qiu: University of Minnesota-Twin Cities
Te-Yueh Lin: University of Minnesota-Twin Cities
Chao Qin: University of Texas Health Science Center at San Antonio
Gail Celio: University Imaging Centers, University of Minnesota-Twin Cities
Peter Yong: University of Minnesota-Twin Cities
Mark Senders: University Imaging Centers, University of Minnesota-Twin Cities
Xianlin Han: University of Texas Health Science Center at San Antonio
David A. Bernlohr: University of Minnesota-Twin Cities
Xiaoli Chen: University of Minnesota-Twin Cities

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.

Date: 2023
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DOI: 10.1038/s41467-023-42473-2

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