Cell biology

A mitochondrial brake on vascular repair

Injured blood vessels are repaired by vascular smooth-muscle cells. It emerges that the protein Fat1 regulates the proliferation of these cells by inhibiting the function of mitochondria. See Letter p.575

After injury to the cells that line blood-vessel walls, vascular smooth-muscle cells (VSMCs) move to the injured region and proliferate to cover the damaged site. However, cellular overproliferation at the repair site might cause vessel-wall thickening that reduces blood flow through the vessel. In addition to naturally occurring damage, blood-vessel injury can be a consequence of surgical interventions such as transplants or procedures to open narrowed blood vessels. An understanding of the signals that regulate VSMC proliferation might enable the development of clinical approaches to limit this process and prevent blood-vessel narrowing. Cao et. al.1 demonstrate on page 575 that the Fat1 receptor protein, a negative regulator of VSMC proliferation, has a direct and unexpected role in regulating energy production in mitochondria, the organelles that act as cellular powerhouses.

Fat1 is a member of the vertebrate Fat cadherins, a small family of proteins whose primary function is unclear2. Previous work3 revealed that Fat1 enhances the migration and limits the proliferation of VSMCs, providing clues that Fat1 could have a role in vascular-cell remodelling.

The Fat1 receptor is normally present at the cell surface, and its structure consists of an extracellular domain, a transmembrane segment and an intracellular domain2. Cao et al. used mass spectrometry to identify proteins that interact with the intracellular domain of mouse Fat1. They discovered that 22 Fat1 interactors are proteins of the inner mitochondrial membrane.

Many biochemists would be cautious about further investigating any such interactions with mitochondrial proteins because nonspecific interactions with these proteins are common. Nonetheless, Cao et al. tested and validated their findings using a variety of techniques. The authors observed that Fat1 is present inside the mitochondria of VSMCs. They also found that non-full-length portions of Fat1 are enriched in mitochondria, and that these portions interact directly with proteins of the mitochondrial respiratory machinery that generate the energy-carrying nucleotide ATP. Subsequent analyses revealed that mouse VSMCs lacking Fat1 had enhanced mitochondrial respiration in the absence of other alterations to mitochondrial structure or mass that might be responsible for such enhancement. Cao and colleagues conclude that Fat1 dampens mitochondrial respiration to suppress VSMC proliferation (Fig. 1).

Figure 1: Fat1 goes with the flow.

Injury to the walls of blood vessels can occur through natural causes or surgical interventions. Vascular smooth-muscle cells (VSMCs) migrate to the damaged site and proliferate as part of the healing response. However, this can result in cellular overproliferation, causing vessel-wall thickening and narrowing the blood vessel. The Fat1 receptor protein (blue) limits the proliferation of VSMCs3. In studies using mice and human cells, Cao et al.1 report that a portion of Fat1 interacts with proteins in the mitochondria and inhibits mitochondrial activity in VSMCs.

The importance of mitochondrial function to the proliferative capacity of VSMCs was already known4. But how central is Fat1 signalling to the mitochondrial regulation needed to enable VSMC repair of vascular damage? Cao et al. established the relevance of this pathway in human tissue through in vitro studies demonstrating that human FAT1 can regulate mitochondrial respiration and proliferation in human VSMCs from arterial blood vessels. The authors also observed FAT1 expression in human VSMCs in an artery-repair context, when they tested post-mortem artery samples from people who had undergone surgical insertion of a stent device to correct atherosclerosis, an artery-narrowing condition.

Cao and colleagues investigated a model of arterial injury using mice whose smooth-muscle cells lacked the Fat1 gene. Injured arteries in these mice became significantly narrower than did those of control mice, establishing that the presence of Fat1 normally limits the potential of VSMCs to contribute to vascular blockage. However, although this model system might be relevant to many aspects of vascular-cell proliferation and remodelling, it does not reflect all the processes involved in vascular disease. Nevertheless, this work establishes a framework with which to further investigate the Fat1 and mitochondrial signalling pathway — for example, by testing whether this mitochondrial-control pathway is evolutionarily conserved in other members of the Fat protein family.

Vascular biology is not the only relevant setting for Fat1 investigation. Roles for Fat1 have been proposed in a surprisingly diverse range of disease states1,2. Cancer is of particular interest, given that studies5 in the fruit fly Drosophila melanogaster indicate that Ft, a fly version of Fat1, is a tumour-suppressor gene. A tumour-suppressor function is consistent with reports of repression or inactivation of FAT1 in certain human cancers2,6 — for example, loss of FAT1 can result in tumour-promoting Wnt-protein signalling6.

However, FAT1 is overexpressed in some types of cancer7, creating a conundrum about whether this protein promotes or inhibits tumours. FAT1 might be overexpressed in cancer because tumour cells need to escape destruction by cell-death processes, and high levels of FAT1 protect against cell death8. FAT1 is also upregulated in low-oxygen (hypoxic) conditions9. The stressful cellular environment that results from hypoxia often occurs in solid tumours, and perhaps FAT1 upregulation allows tumour cells to survive in such conditions. As is so often the case in biology, the determination of a protein's action requires observations to be placed in the correct cellular context. The challenge is to discover whether Fat1's function in controlling mitochondrial respiration is relevant to human cancer.

Many questions remain. Previous work10 shows that D. melanogaster Ft enhances mitochondrial function, which contrasts with Cao and colleagues' observations that Fat1 inhibits mitochondrial function in the mammalian systems they studied. Whether this difference results from evolutionary divergence or reflects a cell-dependent context is unknown.

Discovering how Fat1 is regulated is a key area for further investigation. Cao et al. observed that smaller portions of Fat1, rather than the full-length protein, are associated with the mitochondria. This observation suggests that Fat1 undergoes enzyme-mediated cleavage to enter the mitochondria. Fat1 is a substrate of the γ-secretase protein complex11 — the protease enzyme that cleaves and releases cytoplasmic domains of transmembrane proteins12 — although the authors did not investigate Fat1 cleavage by this or any other enzyme.

It is also not known whether a ligand molecule binds the extracellular domain of Fat1. Given that endothelial cells in blood-vessel walls sense mechanical damage and relay this information to adjacent VSMCs13, endothelial cells might signal to Fat1 by an unknown ligand. An understanding of such aspects of FAT1 regulation will probably be needed for the therapeutic potential of this signalling pathway to be exploited in the clinic.Footnote 1


  1. 1.

    See all news & views


  1. 1

    Cao, L. L. et al. Nature 539, 575–578 (2016).

    CAS  Article  Google Scholar 

  2. 2

    Sadeqzadeh, E., de Bock, C. E. & Thorne, R. F. Med. Res. Rev. 34, 190–221 (2014).

    CAS  Article  Google Scholar 

  3. 3

    Hou, R., Liu, L., Anees, S., Hiroyasu, S. & Sibinga, N. E. S. J. Cell Biol. 173, 417–429 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Chiong, M. et al. Front. Cell Dev. Biol. 2, 72 (2014).

    Article  Google Scholar 

  5. 5

    Mahoney, P. A. et al. Cell 67, 853–868 (1991).

    CAS  Article  Google Scholar 

  6. 6

    Morris, L. G. T. et al. Nature Genet. 45, 253–261 (2013).

    ADS  CAS  Article  Google Scholar 

  7. 7

    de Bock, C. E. et al. Leukemia 26, 918–926 (2012).

    CAS  Article  Google Scholar 

  8. 8

    Kranz, D. & Boutros, M. EMBO J. 33, 181–197 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Madan, E. et al. Int. J. Cancer 139, 2570–2582 (2016).

    CAS  Article  Google Scholar 

  10. 10

    Sing, A. et al. Cell 158, 1293–1308 (2014).

    CAS  Article  Google Scholar 

  11. 11

    Magg, T., Schreiner, D., Solis, G. P., Bade, E. G. & Hofer, H. W. Exp. Cell Res. 307, 100–108 (2005).

    CAS  Article  Google Scholar 

  12. 12

    Bray, S. J. Nature Rev. Mol. Cell Biol. 17, 722–735 (2016).

    CAS  Article  Google Scholar 

  13. 13

    Gao, Y., Chen, T. & Raj, J. U. Am. J. Respir. Cell Mol. Biol. 54, 451–460 (2016).

    CAS  Article  Google Scholar 

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Correspondence to Rick F. Thorne.

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de Bock, C., Thorne, R. A mitochondrial brake on vascular repair. Nature 539, 503–504 (2016). https://doi.org/10.1038/nature20476

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