Letter | Published:

Control of mitochondrial function and cell growth by the atypical cadherin Fat1

Nature volume 539, pages 575578 (24 November 2016) | Download Citation

Abstract

Mitochondrial products such as ATP, reactive oxygen species, and aspartate are key regulators of cellular metabolism and growth. Abnormal mitochondrial function compromises integrated growth-related processes such as development and tissue repair1,2, as well as homeostatic mechanisms that counteract ageing and neurodegeneration3, cardiovascular disease4,5, and cancer6,7. Physiologic mechanisms that control mitochondrial activity in such settings remain incompletely understood. Here we show that the atypical Fat1 cadherin acts as a molecular ‘brake’ on mitochondrial respiration that regulates vascular smooth muscle cell (SMC) proliferation after arterial injury. Fragments of Fat1 accumulate in SMC mitochondria, and the Fat1 intracellular domain interacts with multiple mitochondrial proteins, including critical factors associated with the inner mitochondrial membrane. SMCs lacking Fat1 (Fat1KO) grow faster, consume more oxygen for ATP production, and contain more aspartate. Notably, expression in Fat1KO cells of a modified Fat1 intracellular domain that localizes exclusively to mitochondria largely normalizes oxygen consumption, and the growth advantage of these cells can be suppressed by inhibition of mitochondrial respiration, which suggest that a Fat1-mediated growth control mechanism is intrinsic to mitochondria. Consistent with this idea, Fat1 species associate with multiple respiratory complexes, and Fat1 deletion both increases the activity of complexes I and II and promotes the formation of complex-I-containing supercomplexes. In vivo, Fat1 is expressed in injured human and mouse arteries, and inactivation of SMC Fat1 in mice potentiates the response to vascular damage, with markedly increased medial hyperplasia and neointimal growth, and evidence of higher SMC mitochondrial respiration. These studies suggest that Fat1 controls mitochondrial activity to restrain cell growth during the reparative, proliferative state induced by vascular injury. Given recent reports linking Fat1 to cancer, abnormal kidney and muscle development, and neuropsychiatric disease8,9,10,11,12,13, this Fat1 function may have importance in other settings of altered cell growth and metabolism.

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Acknowledgements

We thank R.N. Kitsis for helpful discussions; A. Jenny for critical reading of the manuscript; X.L. Du for technical help with the Seahorse experiments and for scientific advice; G. Perumal at the Einstein Analytical Imaging Facility for help with electron microscopy imaging; and M.A. Gawinowicz at the Columbia Proteomics laboratory for performing the mass spectrometry analysis. This work was supported by funds from the Diabetes Training and Research Center of Albert Einstein College of Medicine (NIH P60DK20541); funds from the Medical Scientist Training Program (NIH T32-GM007288), Cellular, Molecular Biology, and, Genetics Training Grant (NIH T32-GM007491), and an American Medical Association Seed Grant (all to L.L.C.); from the American Heart Association to D.F.R-B. (pre-doctoral award 11PRE5450002) and to N.E.S.S. (Grant-in-Aid 13GRNT16950064); and from the NIH to L.H. (CA205262) and to N.E.S.S. (HL088104 and HL104518).

Author information

Author notes

    • Rong Hou
    •  & Mario A. Pujato

    Present addresses: Department of Internal Medicine, Division of Infectious Diseases, Allergy, and Immunology, St. Louis University Hospital, St. Louis, Missouri 63104, USA (R.H.); Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA (M.A.P).

    • Longyue L. Cao
    •  & Dario F. Riascos-Bernal

    These authors contributed equally to this work.

Affiliations

  1. Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Longyue L. Cao
    • , Dario F. Riascos-Bernal
    • , Prameladevi Chinnasamy
    • , Charlene M. Dunaway
    • , Rong Hou
    •  & Nicholas E. S. Sibinga
  2. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Longyue L. Cao
    • , Dario F. Riascos-Bernal
    • , Prameladevi Chinnasamy
    • , Charlene M. Dunaway
    • , Rong Hou
    •  & Nicholas E. S. Sibinga
  3. Department of Systems & Computational Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Mario A. Pujato
    •  & Andras Fiser
  4. Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Brian P. O’Rourke
  5. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Veronika Miskolci
    •  & Louis Hodgson
  6. CVPath Institute, Gaithersburg, Maryland 20878, USA

    • Liang Guo
  7. Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Louis Hodgson

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Contributions

L.L.C., D.F.R.-B., P.C., C.M.D., and R.H. generated reagents, performed experiments, and analysed data. B.P.O. performed confocal imaging and analysis of the co-localization studies. V.M. and L.H. imaged and analysed the redox-sensitive ratiometric sensor roGFP. L.G. performed immunohistochemistry on human coronary arteries. M.A.P. and A.F. performed the bioinformatic analysis. L.L.C., D.F.R.-B., and N.E.S.S. designed the study and wrote the paper. L.L.C. and D.F.R.-B. contributed equally to the study. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nicholas E. S. Sibinga.

Reviewer Information

Nature thanks M. Bennett, R. Thorne and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains assembled scans of the uncropped blots.

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DOI

https://doi.org/10.1038/nature20170

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