Li Peng's team revealed that the phospholipid transporter PITPNC1 regulates mitochondrial phospholipid homeostasis to maintain body temperature in mice

On September 23, 2022, the Li Peng team from the Institute of Metabolic and Integrative Biology of Fudan University published a paper
entitled PITPNC1 promotes the thermogenesis of brown adipose tissue under acute cold exposure online in the journal SCIENCE CHINA-Life Sciences 。 PITPNC1 is a class of phospholipid transporters that can transport phosphatidylcholine (PC), phosphatidinositol (PI) and phosphatidic acid (PA) [1-2], the research team studied the physiological regulatory function of this gene through an animal model of Pitpnc1 systemic knockout mice (Pitpnc1-/-), and found that under acute 4 °C cold stimulation, Pitpnc1-^/- mice exhibited a hypothermia intolerance phenotype, until death from hypothermia; Further biochemical tests found that compared with wild-type mice, the blood glucose content of Pitpnc1-/^- mice decreased significantly, and the remaining fat content in brown adipose tissue (BAT) was more, indicating that Pitpnc1-^/- mice normally used blood glucose for thermogenesis, and implied that the deletion of Pitpnc1 gene led to a decrease in the lipid consumption and metabolism ability of BAT, and the thermogenic function of brown adipocytes using fatty acids was impaired.
The importance of
the Pitpnc1 gene in maintaining body temperature in mice under acute cold stimulation was revealed.

In order to explore the pathological mechanism of hypothermia intolerance in Pitpnc1^-/- mice, the research team further investigated four key steps of lipid metabolism function in brown adipocytes: lipid uptake, lipid accumulation, neutral lipid degradation, β oxidation of free fatty acids, etc
.
The results showed that compared with wild-type brown adipocytes, Pitpnc1-/^- brown adipocytes showed no difference in the expression and membrane localization of CD36, the accumulation of lipid droplets after oleic acid treatment, and the release of fatty acids and glycerol after isoprenaline stimulation of neutral fat degradation, but Pitpnc1-^/- brown adipocytes showed a significantly weakened oxygen consumption rate.
The oxygen consumption rate determination of purified mitochondria further confirmed this result
.
In order to further investigate the causes of mitochondrial function defects in Pitpnc1-^/- brown adipocytes, the lipidomics of purified mitochondria showed that PITPNC1 protein deletion led to excessive accumulation of phosphatidylcholine (PC), sphingomyelin (SM) and ceramides (Ceramides) in mitochondria, but there was no significant change
in key proteins (such as Cpt1, COX4, etc.
) on mitochondria.
Excessive accumulation of Ceramides in mitochondria has been reported to limit the β-oxidation of fatty acids in mitochondria ^[3-5].

These results suggest that PITPNC1 protein deletion may lead to dysregulation of mitochondria through defects in phospholipid transport between organelles, ultimately leading to defects in mitochondrial thermogenesis in brown adipocytes (Figure 1).

Figure 1.
The importance of
PITPNC1 protein in regulating mitochondrial lipid homeostasis in maintaining body temperature in mice under acute cold stimulation.
(Left) The body temperature of mice was detected by starving 8-week-old littermates wild-type and Pitpnc1-^/- male mice in single cages for 4 hours at 22°C or 4°C at an interval of 1 hour, and the results showed that PITPNC1 was necessary for mice to maintain body temperature under acute cold exposure; (Right) A schematic of the model demonstrates the importance of
PITPNC1 regulating mitochondrial lipid homeostasis for thermogenesis in brown adipocytes under acute cold stimulation.

Through the above study, the research team revealed for the first time the importance of PITPNC1 protein in maintaining the physiological function of mice under acute cold stimulation, which regulates mitochondrial phospholipid homeostasis, thereby maintaining the mitochondrial thermogenesis function of brown adipocytes, which is of great theoretical significance for the body's regulation of thermogenesis, and the Pitpnc1 gene is expected to be used as a target for the development of new strategies
for the prevention and treatment of metabolic diseases such as obesity.

Dr.
Tang Guoqing and doctoral student Ma Chengxin of the Institute of Metabolic and Integrative Biology of Fudan University are the co-first authors of the paper, and Chen Fengrong, a young researcher from the Institute of Metabolic and Integrative Biology of Fudan University, is the corresponding author
of this study.
At the same time, Professor Wang Ru of Shanghai University of Sport, Yellow River Young Researchers, Professor Zhao Tongjin, Professor Li Peng, Institute of Metabolic and Integrative Biology, Fudan University, and Professor Yang Hongyuan of the University of New South Wales, Australia provided important support
for the research.

Links to papers: https://link.
springer.
com/article/10.
1007/s11427-022-2157-y

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