Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

During autophagy mitochondria elongate, are spared from degradation and sustain cell viability

Nature Cell Biology volume 13, pages 589–598 (2011)Cite this article

Subjects

Abstract

A plethora of cellular processes, including apoptosis, depend on regulated changes in mitochondrial shape and ultrastructure. The role of mitochondria and of their morphology during autophagy, a bulk degradation and recycling process of eukaryotic cells’ constituents, is not well understood. Here we show that mitochondrial morphology determines the cellular response to macroautophagy. When autophagy is triggered, mitochondria elongate in vitro and in vivo. During starvation, cellular cyclic AMP levels increase and protein kinase A (PKA) is activated. PKA in turn phosphorylates the pro-fission dynamin-related protein 1 (DRP1), which is therefore retained in the cytoplasm, leading to unopposed mitochondrial fusion. Elongated mitochondria are spared from autophagic degradation, possess more cristae, increased levels of dimerization and activity of ATP synthase, and maintain ATP production. Conversely, when elongation is genetically or pharmacologically blocked, mitochondria consume ATP, precipitating starvation-induced death. Thus, regulated changes in mitochondrial morphology determine the fate of the cell during autophagy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mitochondrial elongation in response to autophagy.
Figure 2: Increased phosphorylation of Ser 637 of DRP1 during autophagy.
Figure 3: Mitochondrial elongation during starvation is mediated by the cAMP–PKA axis.
Figure 4: Elongated mitochondria are spared from degradation during starvation.
Figure 5: Mitochondrial elongation sustains cellular ATP production and viability during autophagy.
Figure 6: Mitochondrial elongation during starvation is associated with dimerization and activation of ATPase.
Figure 7: Density of cristae increases in mitochondria elongated during starvation.
Figure 8: Mitochondrial elongation induced by PKA determines cell fate during starvation.

Similar content being viewed by others

References

  1. Bereiter-Hahn, J. & Voth, M. Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc. Res. Tech. 27, 198–219 (1994).

    Article  CAS  Google Scholar 

  2. Cipolat, S., de Brito, O. M., Dal Zilio, B. & Scorrano, L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc. Natl Acad. Sci. USA 101, 15927–15932 (2004).

    Article  CAS  Google Scholar 

  3. Santel, A. & Fuller, M. T. Control of mitochondrial morphology by a human mitofusin. J. Cell Sci. 114, 867–874 (2001).

    CAS  PubMed  Google Scholar 

  4. Smirnova, E., Griparic, L., Shurland, D. L. & van der Bliek, A. M. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell 12, 2245–2256 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Cereghetti, G. M. et al. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc. Natl Acad. Sci. USA 105, 15803–15808 (2008).

    Article  CAS  Google Scholar 

  6. Cribbs, J. T. & Strack, S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. 8, 939–944 (2007).

    Article  CAS  Google Scholar 

  7. Chang, C. R. & Blackstone, C. Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J. Biol. Chem. 282, 21583–21587 (2007).

    Article  CAS  Google Scholar 

  8. Harder, Z., Zunino, R. & McBride, H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr. Biol. 14, 340–345 (2004).

    Article  CAS  Google Scholar 

  9. Braschi, E., Zunino, R. & McBride, H. M. MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Rep. 10, 748–754 (2009).

    Article  CAS  Google Scholar 

  10. Scorrano, L. et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev. Cell 2, 55–67 (2002).

    Article  CAS  Google Scholar 

  11. Martinou, I. et al. The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event. J. Cell Biol. 144, 883–889 (1999).

    Article  CAS  Google Scholar 

  12. Frank, S. et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515–525 (2001).

    Article  CAS  Google Scholar 

  13. Szabadkai, G. et al. Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis. Mol. Cell 16, 59–68 (2004).

    Article  CAS  Google Scholar 

  14. Li, Z., Okamoto, K., Hayashi, Y. & Sheng, M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119, 873–887 (2004).

    Article  CAS  Google Scholar 

  15. Campello, S. et al. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J. Exp. Med. 203, 2879–2886 (2006).

    Article  CAS  Google Scholar 

  16. Mitra, K., Wunder, C., Roysam, B., Lin, G. & Lippincott-Schwartz, J. A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc. Natl Acad. Sci. USA 106, 11960–11965 (2009).

    Article  CAS  Google Scholar 

  17. Scheckhuber, C. Q. et al. Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models. Nat. Cell Biol. 9, 99–105 (2007).

    Article  CAS  Google Scholar 

  18. Twig, G. et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433–446 (2008).

    Article  CAS  Google Scholar 

  19. Gomes, L. C. & Scorrano, L. High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy. Biochim. Biophys. Acta 1777, 860–866 (2008).

    Article  CAS  Google Scholar 

  20. Klionsky, D. J. & Emr, S. D. Autophagy as a regulated pathway of cellular degradation. Science 290, 1717–1721 (2000).

    Article  CAS  Google Scholar 

  21. Cecconi, F. & Levine, B. The role of autophagy in mammalian development: cell makeover rather than cell death. Dev. Cell 15, 344–357 (2008).

    Article  CAS  Google Scholar 

  22. Ravikumar, B., Duden, R. & Rubinsztein, D. C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002).

    Article  CAS  Google Scholar 

  23. Zheng, Y. T. et al. The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J. Immunol. 183, 5909–5916 (2009).

    Article  CAS  Google Scholar 

  24. Tuttle, D. L., Lewin, A. S. & Dunn, W. A. Jr Selective autophagy of peroxisomes in methylotrophic yeasts. Eur. J. Cell Biol. 60, 283–290 (1993).

    CAS  PubMed  Google Scholar 

  25. Bernales, S., McDonald, K. L. & Walter, P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4, e423 (2006).

    Article  Google Scholar 

  26. Elmore, S. P., Qian, T., Grissom, S. F. & Lemasters, J. J. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J. 15, 2286–2287 (2001).

    Article  CAS  Google Scholar 

  27. Tooze, S. A. & Yoshimori, T. The origin of the autophagosomal membrane. Nat. Cell Biol. 12, 831–835 (2010).

    CAS  PubMed  Google Scholar 

  28. Scherz-Shouval, R. et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26, 1749–1760 (2007).

    Article  CAS  Google Scholar 

  29. Hailey, D. W. et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141, 656–667 (2010).

    Article  CAS  Google Scholar 

  30. de Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610 (2008).

    Article  Google Scholar 

  31. Karbowski, M. et al. Quantitation of mitochondrial dynamics by photolabelling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J. Cell Biol. 164, 493–499 (2004).

    Article  CAS  Google Scholar 

  32. Song, Z., Chen, H., Fiket, M., Alexander, C. & Chan, D. C. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J. Cell Biol. 178, 749–755 (2007).

    Article  CAS  Google Scholar 

  33. Chen, H., Chomyn, A. & Chan, D. C. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J. Biol. Chem. 280, 26185–26192 (2005).

    Article  CAS  Google Scholar 

  34. Ishihara, N. et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat. Cell Biol. 11, 958–966 (2009).

    Article  CAS  Google Scholar 

  35. Jouaville, L. S., Pinton, P., Bastianutto, C., Rutter, G. A. & Rizzuto, R. Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc. Natl Acad. Sci. USA 96, 13807–13812 (1999).

    Article  CAS  Google Scholar 

  36. Rich, P. Chemiosmotic coupling: the cost of living. Nature 421, 583 (2003).

    Article  CAS  Google Scholar 

  37. Strauss, M., Hofhaus, G., Schroder, R. R. & Kuhlbrandt, W. Dimer ribbons of ATP synthase shape the inner mitochondrial membrane. EMBO J. 27, 1154–1160 (2008).

    Article  CAS  Google Scholar 

  38. Giraud, M. F. et al. Is there a relationship between the supramolecular organization of the mitochondrial ATP synthase and the formation of cristae? Biochim. Biophys. Acta 1555, 174–180 (2002).

    Article  CAS  Google Scholar 

  39. Unger, R. H. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia 28, 574–578 (1985).

    Article  CAS  Google Scholar 

  40. Pan, X. & Heitman, J. Cyclic AMP-dependent protein kinase regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Mol. Cell Biol. 19, 4874–4887 (1999).

    Article  CAS  Google Scholar 

  41. Budovskaya, Y. V., Stephan, J. S., Reggiori, F., Klionsky, D. J. & Herman, P. K. The Ras/cAMP-dependent protein kinase signalling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae. J. Biol. Chem. 279, 20663–20671 (2004).

    Article  CAS  Google Scholar 

  42. Stephan, J. S., Yeh, Y. Y., Ramachandran, V., Deminoff, S. J. & Herman, P. K. The Tor and PKA signalling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy. Proc. Natl Acad. Sci. 106, 17049–17054 (2009).

    Article  CAS  Google Scholar 

  43. Mavrakis, M., Lippincott-Schwartz, J., Stratakis, C. A. & Bossis, I. Depletion of type IA regulatory subunit (RIalpha) of protein kinase A (PKA) in mammalian cells and tissues activates mTOR and causes autophagic deficiency. Hum. Mol. Genet. 15, 2962–2971 (2006).

    Article  CAS  Google Scholar 

  44. Slattery, M. G., Liko, D. & Heideman, W. Protein kinase A, TOR, and glucose transport control the response to nutrient repletion in Saccharomyces cerevisiae. Eukaryot. Cell 7, 358–367 (2008).

    Article  CAS  Google Scholar 

  45. Tondera, D. et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 28, 1589–1600 (2009).

    Article  CAS  Google Scholar 

  46. Karbowski, M. & Youle, R. J. Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ. 10, 870–880 (2003).

    Article  CAS  Google Scholar 

  47. Cereghetti, G. M., Costa, V. & Scorrano, L. Inhibition of Drp1-dependent mitochondrial fragmentation and apoptosis by a polypeptide antagonist of calcineurin. Cell Death Differ. 17, 1785–1794 (2010).

    Article  CAS  Google Scholar 

  48. Wasiak, S., Zunino, R. & McBride, H. M. Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J. Cell Biol. 177, 439–450 (2007).

    Article  CAS  Google Scholar 

  49. Nakamura, N., Kimura, Y., Tokuda, M., Honda, S. & Hirose, S. MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep. 7, 1019–1022 (2006).

    Article  CAS  Google Scholar 

  50. Karbowski, M., Neutzner, A. & Youle, R. J. The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J. Cell Biol. 178, 71–84 (2007).

    Article  CAS  Google Scholar 

  51. Tanaka, A. et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191, 1367–1380 (2010).

    Article  CAS  Google Scholar 

  52. Ziviani, E., Tao, R. N. & Whitworth, A. J. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc. Natl Acad. Sci. USA 107, 5018–5023 (2010).

    Article  CAS  Google Scholar 

  53. Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008).

    Article  CAS  Google Scholar 

  54. Costa, V. et al. Mitochondrial fission and cristae disruption increase the response of cell models of Huntington’s disease to apoptotic stimuli. EMBO Mol. Med. 2, 490–503 (2010).

    Article  CAS  Google Scholar 

  55. Brown, G. C. Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochem. J. 284, 1–13 (1992).

    Article  CAS  Google Scholar 

  56. Frezza, C. et al. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126, 177–189 (2006).

    Article  CAS  Google Scholar 

  57. Meeusen, S. et al. Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell 127, 383–395 (2006).

    Article  CAS  Google Scholar 

  58. Mopert, K. et al. Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization. Exp. Cell Res. 315, 2165–2180 (2009).

    Article  Google Scholar 

  59. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    Article  CAS  Google Scholar 

  60. Nikolaev, V. O., Bünemann, M., Hein, L., Hannawacker, A. & Lohse, M. J. Novel single chain cAMP sensors for receptor-induced signal propagation. J. Biol. Chem. 279, 37215–37218 (2004).

    Article  CAS  Google Scholar 

  61. de Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610 (2008).

    Article  Google Scholar 

  62. Scorrano, L. et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300, 135–139 (2003).

    Article  CAS  Google Scholar 

  63. Danial, N. N. et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952–956 (2003).

    Article  CAS  Google Scholar 

  64. Frezza, C., Cipolat, S. & Scorrano, L. Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts. Nat. Protoc. 2, 287–295 (2007).

    Article  CAS  Google Scholar 

  65. Alirol, E. et al. The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis. Mol. Biol. Cell 17, 4593–4605 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

L.C.G. is the recipient of a ‘Bolsa de Doutoramento’ of the ‘Fundação para a Ciência e Tecnologia’, Portugal. L.S. is a Senior Telethon Scientist of the Dulbecco-Telethon Institute. This research was supported by Telethon Italy S02016, AIRC Italy, Swiss National Foundation SNF 31-118171. We thank D. Chan, K. Mihara, C. Blackstone and N. Mizushima for reagents and T. Pozzan for helpful discussions on mitochondrially targeted luciferase calibration.

Author information

Authors and Affiliations

  1. Dulbecco-Telethon Institute, Via Orus 2, 35129 Padova, Italy

    Ligia C. Gomes & Luca Scorrano

  2. Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy

    Ligia C. Gomes, Giulietta Di Benedetto & Luca Scorrano

  3. PhD Programme in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal

    Ligia C. Gomes

  4. CNR Institute for Neurosciences, Section of Padova, Via G. Colombo 3, 35129 Padova, Italy

    Giulietta Di Benedetto

  5. Department of Cell Physiology and Medicine, University of Geneva, 1 Rue M. Servet, 1211 Geneve, Switzerland

    Luca Scorrano

Authors
  1. Ligia C. Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giulietta Di Benedetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luca Scorrano
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.C.G. and L.S. conceived research, analysed data and wrote the manuscript. L.C.G., G.D.B. and L.S. carried out experiments and analysed data.

Corresponding author

Correspondence to Luca Scorrano.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1256 kb)

Supplementary Movie 1

Supplementary Information (MOV 6000 kb)

Supplementary Movie 2

Supplementary Information (MOV 6000 kb)

Supplementary Movie 3

Supplementary Information (MOV 18063 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gomes, L., Benedetto, G. & Scorrano, L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13, 589–598 (2011). https://doi.org/10.1038/ncb2220

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2220

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing
pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy