Autophagy protects kidney proximal tubule epithelial cells from mitochondrial metabolic stress

Tomonori Kimura, Atsushi Takahashi, Yoshitsugu Takabatake, Tomoko Namba, Takeshi Yamamoto, Jun Kaimori, Isao Matsui, Harumi Kitamura, Fumio Niimura, Taiji Matsusaka, Tomoyoshi Soga, Hiromi Rakugi, Yoshitaka Isaka

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Chronic metabolic stress is related to diseases, whereas autophagy supplies nutrients by recycling the degradative products. cyclosporin A (csA), a frequently used immunosuppressant, induces metabolic stress via effects on mitochondrial respiration, and thereby, its chronic usage is often limited. here we show that autophagy plays a protective role against csA-induced metabolic stress in kidney proximal tubule epithelial cells. Autophagy deficiency leads to decreased mitochondrial membrane potential, which coincides with metabolic abnormalities as characterized by decreased levels of amino acids, increased tricarboxylic acid (TcA) ratio (the levels of intermediates of the latter part of the TcA cycle, over levels of intermediates in the earlier part), and decreased products of oxidative phosphorylation (ATP). In addition to the altered profile of amino acids, csA decreased the hyperpolarization of mitochondria with the disturbance of mitochondrial energy metabolism in autophagy-competent cells, i.e., increased TcA ratio and worsening of the NAD+/NADh ratio, coupled with decreased energy status, which suggests that adaptation to csA employs autophagy to supply electron donors from amino acids via intermediates of the latter part of the TcA cycle. The TcA ratio of autophagy-deficient cells was further worsened with decreased levels of amino acids in response to csA, and, as a result, the deficiency of autophagy failed to adapt to the csA-induced metabolic stress. Deterioration of the TcA ratio further worsened energy status. The csA-induced metabolic stress also activated regulatory genes of metabolism and apoptotic signals, whose expressions were accelerated in autophagy-deficient cells. These data provide new perspectives on autophagy in conditions of chronic metabolic stress in disease.

Original languageEnglish
Pages (from-to)1876-1886
Number of pages11
JournalAutophagy
Volume9
Issue number11
DOIs
Publication statusPublished - 2013 Nov

Keywords

  • Autophagy
  • Chronic kidney disease
  • Cyclosporin A
  • Kidney proximal tubule
  • Metabolic stress
  • Mitochondria

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Kimura, T., Takahashi, A., Takabatake, Y., Namba, T., Yamamoto, T., Kaimori, J., Matsui, I., Kitamura, H., Niimura, F., Matsusaka, T., Soga, T., Rakugi, H., & Isaka, Y. (2013). Autophagy protects kidney proximal tubule epithelial cells from mitochondrial metabolic stress. Autophagy, 9(11), 1876-1886. https://doi.org/10.4161/auto.25418