Involvement of mitophagy in oncogenic K-Ras-induced transformation: Overcoming a cellular energy deficit from glucose deficiency

June Hyung Kim, Hee Young Kim, Young Kyoung Lee, Young Sil Yoon, Wei Guang Xu, Joon Kee Yoon, Sung E. Choi, Young-Gyu Ko, Min Jung Kim, Su Jae Lee, Hee Jung Wang, Gyesoon Yoon

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Although mitochondrial impairment has often been implicated in carcinogenesis, the mechanisms of its development in cancer remain unknown. We report here that autophagy triggered by oncogenic K-Ras mediates functional loss of mitochondria during cell transformation to overcome an energy deficit resulting from glucose deficiency. When Rat2 cells were infected with a retrovirus harboring constitutively active K-Ras V12, mitochondrial respiration significantly declined in parallel with the acquisition of transformation characteristics. Decreased respiration was not related to mitochondrial biogenesis but was inversely associated with the increased formation of acidic vesicles enclosing mitochondria, during which autophagy-related proteins such as Beclin 1, Atg5, LC3-II and vacuolar ATPases were induced. Interestingly, blocking autophagy with conventional inhibitors (bafilomycin A, 3-methyladenin) and siRNA-mediated knockdown of autophagy-related genes recovered respiratory protein expression and respiratory activity; JNK was involved in these phenomena as an upstream regulator. The cells transformed by K-Ras V12 maintained cellular ATP level mainly through glycolytic ATP production without induction of GLUT1, the low K m glucose transporter. Finally, K-Ras V12-triggered LC3-II formation was modulated by extracellular glucose levels, and LC3-II formation increased only in hepatocellular carcinoma tissues exhibiting low glucose uptake and increased K-Ras expression. Taken together, our observations suggest that mitochondrial functional loss may be mediated by oncogenic K-Ras-induced mitophagy during early tumorigenesis even in the absence of hypoxia, and that this mitophagic process may be an important strategy to overcome the cellular energy deficit triggered by insufficient glucose.

Original languageEnglish
Pages (from-to)1187-1198
Number of pages12
JournalAutophagy
Volume7
Issue number10
DOIs
Publication statusPublished - 2011 Oct 1

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Mitochondrial Degradation
Autophagy
Glucose
Mitochondria
Respiration
Carcinogenesis
Adenosine Triphosphate
Vacuolar Proton-Translocating ATPases
Facilitative Glucose Transport Proteins
Organelle Biogenesis
Retroviridae
Small Interfering RNA
Hepatocellular Carcinoma
Genes
Neoplasms
Proteins

Keywords

  • Cell transformation
  • Energy deficit
  • K-Ras
  • Mitochondrial loss
  • Mitophagy

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Involvement of mitophagy in oncogenic K-Ras-induced transformation : Overcoming a cellular energy deficit from glucose deficiency. / Kim, June Hyung; Kim, Hee Young; Lee, Young Kyoung; Yoon, Young Sil; Xu, Wei Guang; Yoon, Joon Kee; Choi, Sung E.; Ko, Young-Gyu; Kim, Min Jung; Lee, Su Jae; Wang, Hee Jung; Yoon, Gyesoon.

In: Autophagy, Vol. 7, No. 10, 01.10.2011, p. 1187-1198.

Research output: Contribution to journalArticle

Kim, JH, Kim, HY, Lee, YK, Yoon, YS, Xu, WG, Yoon, JK, Choi, SE, Ko, Y-G, Kim, MJ, Lee, SJ, Wang, HJ & Yoon, G 2011, 'Involvement of mitophagy in oncogenic K-Ras-induced transformation: Overcoming a cellular energy deficit from glucose deficiency', Autophagy, vol. 7, no. 10, pp. 1187-1198. https://doi.org/10.4161/auto.7.10.16643
Kim, June Hyung ; Kim, Hee Young ; Lee, Young Kyoung ; Yoon, Young Sil ; Xu, Wei Guang ; Yoon, Joon Kee ; Choi, Sung E. ; Ko, Young-Gyu ; Kim, Min Jung ; Lee, Su Jae ; Wang, Hee Jung ; Yoon, Gyesoon. / Involvement of mitophagy in oncogenic K-Ras-induced transformation : Overcoming a cellular energy deficit from glucose deficiency. In: Autophagy. 2011 ; Vol. 7, No. 10. pp. 1187-1198.
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AB - Although mitochondrial impairment has often been implicated in carcinogenesis, the mechanisms of its development in cancer remain unknown. We report here that autophagy triggered by oncogenic K-Ras mediates functional loss of mitochondria during cell transformation to overcome an energy deficit resulting from glucose deficiency. When Rat2 cells were infected with a retrovirus harboring constitutively active K-Ras V12, mitochondrial respiration significantly declined in parallel with the acquisition of transformation characteristics. Decreased respiration was not related to mitochondrial biogenesis but was inversely associated with the increased formation of acidic vesicles enclosing mitochondria, during which autophagy-related proteins such as Beclin 1, Atg5, LC3-II and vacuolar ATPases were induced. Interestingly, blocking autophagy with conventional inhibitors (bafilomycin A, 3-methyladenin) and siRNA-mediated knockdown of autophagy-related genes recovered respiratory protein expression and respiratory activity; JNK was involved in these phenomena as an upstream regulator. The cells transformed by K-Ras V12 maintained cellular ATP level mainly through glycolytic ATP production without induction of GLUT1, the low K m glucose transporter. Finally, K-Ras V12-triggered LC3-II formation was modulated by extracellular glucose levels, and LC3-II formation increased only in hepatocellular carcinoma tissues exhibiting low glucose uptake and increased K-Ras expression. Taken together, our observations suggest that mitochondrial functional loss may be mediated by oncogenic K-Ras-induced mitophagy during early tumorigenesis even in the absence of hypoxia, and that this mitophagic process may be an important strategy to overcome the cellular energy deficit triggered by insufficient glucose.

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