Who is the porter in heme “logistics”? Scientists reveal important mechanisms of heme transport within cells

Group photo of the research team. (Photo courtesy of Zhejiang University)

Blood appears red because of the presence of heme in red blood cells. Don’t think heme is just a “stain”, it is actually a necessary life factor.

On October 19, the team of Professor Chen Caiyong of the School of Life Sciences of Zhejiang University published a research paper in Nature to reveal the important mechanism of intracellular heme transport. The study found a family of heme chaperones whose members HRG-9, HRG-10 and TANGO2 transport heme to heme storage sites or synthetic sites for use at other subcellular sites. Nature published a research brief in the same period, presenting and commenting on the findings.

Heme is responsible for the transport of oxygen in the blood and participates in biological processes such as cellular respiration, signal transduction, gene expression regulation, and circadian rhythm regulation. Insufficient heme can cause anemia and porphyria, while too much or poorly disposed heme can be toxic and increase the risk of cancer, metabolic diseases, and cardiovascular disease. For this reason, it is necessary to identify the “logistics” channels for the transport of heme.

As early as the 50s of the last century, scientists had in-depth research on the synthetic pathway of heme. But until now, the heme transport pathway within cells has been unclear, and one important reason is that it is difficult to distinguish the proteins that transport heme from the regulators of heme synthesis.

“To study heme can be described as involving the whole body.” Chen Caiyong, the corresponding author of the paper, said that the heme synthesis and transport process in cells is regulated by a variety of factors, and it is difficult to bypass the manufacturing process to study the transport problem, and if the transport factor is changed, it is likely to be fed back by the synthesis related factors, affecting the heme level in the cell, thereby interfering with the experimental results.

In order to solve this research problem, Chen Caiyong’s laboratory carried out research on heme transport through the model animal of C. elegans. Unlike most organisms, C. elegans cannot synthesize heme itself, but it needs heme to maintain life activities. Chen Caiyong introduced that the heme in the nematode body comes entirely from food, and then stores it in the “warehouse” of lysosome-related organelles and transports it to the required parts, so it provides an ideal model for the study of heme transport pathways.

The team divided C. elegans into multiple groups, exposed to high-concentration, suitable concentration and low concentrations of heme, and by analyzing the expression pattern of nematode genes, they found an unknown gene, whose expression is regulated by heme. The team named this gene HRG-9 (heme responsive gene-9), and there is another gene on the nematode that is similar to HRG-9, named HRG-10.

“Our research found that this is the ‘porter’ in the intracellular heme ‘logistics’.” Chen Caiyong said that in C. elegans, HRG-9 and HRG-10 are mainly responsible for mobilizing and using heme to transport heme out of the “warehouse”. When HRG-9 or HRG-10 is absent in nematodes, heme accumulates at the storage site, while heme is lacking elsewhere in the cell.

Through analysis, Chen Caiyong’s laboratory found that among the organisms that can synthesize heme, there is a gene similar to hrg-9 called TANGO2. The gene was originally thought to be involved in protein secretion and Golgi structure.

Using a variety of research systems and experimental methods, the researchers found that TANGO2 in yeast, zebrafish and mammals can also transport heme. In the cells of these organisms, TANGO2 transports heme directly from the mitochondria, the “factory” that makes heme, to facilitate the utilization of heme.

It has been shown that mutations in the human TANGO2 gene cause a rare genetic disease. Patients have been reported to be young children or children, with a variety of symptoms such as developmental delay, rhabdomyolysis, arrhythmias, epilepsy, and metabolic syndrome.

“In the past, due to the lack of understanding of TANGO2 function, the cause of TANGO2 mutation caused by disease was still unclear.” Speaking about the future, Chen Caiyong introduced the results to provide an important foundation for understanding the pathological mechanism of TANGO2 disease and exploring treatment strategies for the disease.

“We found that tango2 in zebrafish is also critical for early growth and development.” After knocking out tango2 on zebrafish, juveniles showed encephalopathy, irregular heartbeats, muscle damage, and died early in development, pathological symptoms similar to those of diseased children, he said. “This provides a disease model for studying the pathogenesis and treatment strategies of TANGO2 disease.”

The research was supported by the National Foundation of China, the Ministry of Science and Technology, and the Cancer Research Institute of Zhejiang University. (Source: Cui Xueqin, China Science Daily)

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