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The Role of Mitochondrial Dynamics in Ras-driven Cancers

, by David Kashatus

David Kashatus

David Kashatus, Ph.D. (Dan Addison | UVA)

David Kashatus earned his Ph.D. with Albert Baldwin at the University of North Carolina, and did a postdoc with Christopher Counter at Duke University. He is Associate Professor at the University of Virginia School of Medicine.

The nearly universal tendency of tumor cells to exhibit increased glucose uptake and lactate secretion led to the assumption that mitochondria were not major players in the tumorigenic process.  Indeed, Otto Warburg’s erroneous conclusion from his seminal work defining this metabolic shift was that “The driving force of the increase of fermentation, however, is the energy deficiency under which the cells operate after destruction of their respiration, which forces the cells to replace the irretrievably lost respiration energy in some way.” (1).  As our understanding of tumor metabolism has evolved since those early days, so too has the appreciation for the multiple ways in which mitochondria participate in the multiple metabolic alterations required to support rapid proliferation.  In parallel, mitochondria are no longer seen as static beans floating in the cytoplasm. We now see mitochondria as dynamic structures, changing shape and fusing and dividing and moving throughout the cell to rapidly adapt to cellular needs.  It should come as no surprise, therefore, that potent oncogenes such as RAS coopt the machinery that drives mitochondrial fusion and fission.  In support of this, several studies have come out in the past 5 years demonstrating how RAS, and other oncogenes such as MYC, remodel the mitochondrial network and how this shift in mitochondrial shape plays a key role in tumor growth.

Thematic graphic depicting the fusion and fission of mitochondria in a cell.

Observations that mitochondrial shape is different in tumor cells started emerging around 10 years ago (2,3) and the first evidence that altering mitochondrial shape could impact tumor cell growth and survival followed shortly after (4,5).  Only in the last 5 years however has solid evidence emerged that mitochondrial shape changes are direct consequences of oncogene activation.  In 2015, our lab and the lab of Jerry Chipuk demonstrated that expression of oncogenic RAS and RAF lead to mitochondrial fragmentation through phosphorylation and activation of the mitochondrial fission GTPase Drp1 by Erk (6,7).  In parallel, the lab of Luca Scorrano showed that Erk phosphorylates and inactivates the mitochondrial fusion GTPase Mfn1 (8).  These studies demonstrated that this regulated shift towards a fragmented mitochondrial phenotype was required for cellular transformation in vitro and that its inhibition could block subcutaneous xenograft growth, suggesting that mitochondrial shape might be playing an important role in RAS- and MAPK-driven cancers in vivo.  This prediction has been borne out by a number of publications in the last year demonstrating the importance of mitochondrial dynamics in KRAS-driven pancreatic cancer and revealing how this morphological shift is fundamental to Ras-driven metabolic reprogramming (9-11).

One function of mitochondrial fission is thought to be to generate smaller mitochondrial units that can more efficiently be removed through selective autophagy (mitophagy).  Recent work from the Tuveson lab demonstrated that expression of oncogenic KRas leads to increased expression of the mitophagy receptor Nix (11).  In a series of elegant experiments performed in tumor organoids and with a variety of mouse models, they demonstrated that increased Nix-mediated mitophagy leads to decreased mitochondrial metabolism and a shift towards glycolysis.  Further, inhibition of Nix leads to decreased proliferation under glucose-limiting conditions and decreased tumor initiation in vivo.  Although tumors eventually form in the absence of Nix, the upregulation of alternative mitophagy pathways in these tumors highlights how important mitophagy is in Ras-driven tumor growth.  Consistent with these findings, work from our lab recently demonstrated that Drp1-dependent mitochondrial fragmentation also supports a glycolytic shift in KRas-driven pancreatic cancer cell lines and KRASG12D-expressing MEFs (9).  Surprisingly, we showed that Drp1, and presumably mitochondrial fission, are required for Ras-induced Hexokinase 2 (HK2) expression and that restoration of HK2 could completely rescue the glycolytic defect observed upon Drp1 deletion.  Also, as the Tuveson lab observed with Nix depletion, deletion of Drp1 led to increased survival in an autochthonous model of PDAC.  However, similar to what they saw in their model, we observed that long term ablation of Drp1 eventually led to the emergence of tumor cells with restored glycolytic flux.  Importantly though, these cells demonstrated decreased mitochondrial function, likely due to the loss of the turnover of damaged mitochondria.  Just prior to the publication of our work, a similar study was published by the lab of Cullen Taniguchi (10).  Consistent with our study, they observed that inhibition of Ras-induced mitochondrial fission led to a loss of KRas-driven transformation and pancreatic tumor growth.  They also observed that the promotion of mitochondrial lengthening led to decreased mitochondrial function.  Importantly, their work also demonstrated that this requirement can be exploited pharmacologically using the FDA-approved arthritis drug leflunomide, which was recently shown to be an agonist for the fusion GTPase Mfn2 and to promote mitochondrial elongation (12).

Collectively, these three studies argue that mitochondrial fission and mitophagy may be attractive targets for pancreatic cancer and other Ras-driven malignancies.  Furthermore, they demonstrate how the importance of mitochondria extends beyond oxidative metabolism and how manipulation of mitochondrial structure and function can have important metabolic impacts outside of the mitochondria.  It should be noted that the regulation of mitochondrial shape in cancer is not limited to Ras-driven cancers.  Studies from the labs of Dario Altieri and Martin Eilers have revealed that oncogenic Myc can also regulate mitochondrial shape to promote a variety of important tumorigenic properties (13,14).  Furthermore, Kris Wood and colleagues recently showed that mitochondrial dynamics are dysregulated in a variety of malignancies, leading to specific and exploitable drug sensitivities (15).  Hopefully, this burst in research linking mitochondrial shape and tumor growth will spur a similar burst in the development of small molecules capable of selectively targeting the mitochondrial dynamics machinery, as this looks to be a promising new avenue in the fight against cancer.

Selected References
  1. Warburg O, 1956. On the origin of cancer cells. Science

    [PubMed Abstract]
  2. Arismendi-Morillo G, 2009. Electron microscopy morphology of the mitochondrial network in human cancer. Int J Biochem Cell Biol

    [PubMed Abstract]
  3. Plecitá-Hlavatá L, Lessard M, Santorová J, Bewersdorf J, Jezek P, 2008. Mitochondrial oxidative phosphorylation and energetic status are reflected by morphology of mitochondrial network in INS-1E and HEP-G2 cells viewed by 4Pi microscopy. Biochim Biophys Acta

    [PubMed Abstract]
  4. Rehman J, Zhang HJ, Toth PT, Zhang Y, Marsboom G, Hong Z, Salgia R, Husain AN, Wietholt C, Archer SL, 2012. Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J

    [PubMed Abstract]
  5. Inoue-Yamauchi A, Oda H, 2012. Depletion of mitochondrial fission factor DRP1 causes increased apoptosis in human colon cancer cells. Biochem Biophys Res Commun

    [PubMed Abstract]
  6. Serasinghe MN, Wieder SY, Renault TT, Elkholi R, Asciolla JJ, Yao JL, Jabado O, Hoehn K, Kageyama Y, Sesaki H, Chipuk JE, 2015. Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell

    [PubMed Abstract]
  7. Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL, Counter CM, Kashatus DF, 2015. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell

    [PubMed Abstract]
  8. Pyakurel A, Savoia C, Hess D, Scorrano L, 2015. Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis. Mol Cell

    [PubMed Abstract]
  9. Nagdas S, Kashatus JA, Nascimento A, Hussain SS, Trainor RE, Pollock SR, Adair SJ, Michaels AD, Sesaki H, Stelow EB, Bauer TW, Kashatus DF, 2019.  Drp1 Promotes KRas-Driven Metabolic Changes to Drive Pancreatic Tumor Growth. Cell Rep

    [PubMed Abstract]
  10. Yu M, Nguyen ND, Huang Y, Lin D, Fujimoto TN, Molkentine JM, Deorukhkar A, Kang Y, San Lucas FA, Fernandes CJ, Koay EJ, Gupta S, Ying H, Koong AC, Herman JM, Fleming JB, Maitra A, Taniguchi CM, 2019. Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer. JCI Insight

    [PubMed Abstract]
  11. Humpton TJ, Alagesan B, DeNicola GM, Lu D, Yordanov GN, Leonhardt CS, Yao MA, Alagesan P, Zaatari MN, Park Y, Skepper JN, Macleod KF, Perez-Mancera PA, Murphy MP, Evan GI, Vousden KH, Tuveson DA, 2019.  Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer. Cancer Discov

    [PubMed Abstract]
  12. Miret-Casals L, Sebastián D, Brea J, Rico-Leo EM, Palacín M, Fernández-Salguero PM, Loza MI, Albericio F, Zorzano A, 2018. Identification of New Activators of Mitochondrial Fusion Reveals a Link between Mitochondrial Morphology and Pyrimidine Metabolism. Cell Chem Biol

    [PubMed Abstract]
  13. von Eyss B, Jaenicke LA, Kortlever RM, Royla N, Wiese KE, Letschert S, McDuffus LA, Sauer M, Rosenwald A, Evan GI, Kempa S, Eilers M, 2015. A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer. Cancer Cell

    [PubMed Abstract]
  14. Agarwal E, Altman BJ, Ho Seo J, Bertolini I, Ghosh JC, Kaur A, Kossenkov AV, Languino LR, Gabrilovich DI, Speicher DW, Dang CV, Altieri DC, 2019. Myc Regulation of a Mitochondrial Trafficking Network Mediates Tumor Cell Invasion and Metastasis. Mol Cell Biol

    [PubMed Abstract]
  15. Anderson GR, Wardell SE, Cakir M, Yip C, Ahn YR, Ali M, Yllanes AP, Chao CA, McDonnell DP, Wood KC, 2018. Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors. Nat Commun

    [PubMed Abstract]
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