Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-α

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Distelmaier, Felix^1,2,3  Valsecchi, Federica^1,2  Liemburg-Apers, Dania C.¹  Lebiedzinska, Magdalena⁴  Rodenburg, Richard J.²  Heil, Sandra⁵  Keijer, Jaap⁵  Fransen, Jack⁶  Imamura, Hiromi⁷  Danhauser, Katharina³  Seibt, Annette³  Viollet, Benoit⁸  Gellerich, Frank N.⁹  Smeitink, Jan A. M.²  Wieckowski, Mariusz R.⁴  Willems, Peter H. G. M.¹  Koopman, Werner J. H.¹ 

[1] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Biochem, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Nijmegen Ctr Mitochondrial Disorders, Dept Pediat, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[3] Univ Dusseldorf, Univ Childrens Hosp, Dept Gen Pediat Neonatol & Pediat Cardiol, D-40225 Dusseldorf, Germany

[4] M Nencki Inst Expt Biol, PL-02093 Warsaw, Poland

[5] Wageningen Univ, Dept Human & Anim Physiol, NL-6708 WD Wageningen, Netherlands

[6] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Cell Biol, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[7] Kyoto Univ, Hakubi Project, Kyoto 6068501, Japan

[8] Univ Paris 05, NSERM U1016, Inst Cochin, F-75014 Paris, France

[9] Otto Von Guericke Univ, Dept Stereotact Neurosurg, D-39120 Magdeburg, Germany

关键词: Respirometry;    glycolysis;    redox signaling;    mitochondrial dynamics;    metabolic regulation;    calcium homeostasis;   

DOI  :  10.1016/j.bbadis.2014.12.012

来源: Elsevier

【 摘 要 】

Dysfunction of complex I (CI) of the mitochondrial electron transport chain (ETC) features prominently in human pathology. Cell models of ETC dysfunction display adaptive survival responses that still are poorly understood but of relevance for therapy development Here we comprehensively examined how primary human skin fibroblasts adapt to chronic CI inhibition. CI inhibition triggered transient and sustained changes in metabolism, redox homeostasis and mitochondrial (ultra)structure but no cell senescence/death. CI-inhibited cells consumed no oxygen and displayed minor mitochondrial depolarization, reverse-mode action of complex V, a slower proliferation rate and futile mitochondrial biogenesis. Adaptation was neither prevented by antioxidants nor associated with increased PGC1-alpha/SIRT1/mTOR levels. Survival of CI-inhibited cells was strictly glucose-dependent and accompanied by increased AMPK-alpha phosphorylation, which occurred without changes in ATP or cytosolic calcium levels. Conversely, cells devoid of AMPK-alpha died upon CI inhibition. Chronic CI inhibition did not increase mitochondrial superoxide levels or cellular lipid peroxidation and was paralleled by a specific increase in SOD2/GR, whereas SOD1/CAT/Gpx1/Gpx2/Gpx5 levels remained unchanged. Upon hormone stimulation, fully adapted cells displayed aberrant cytosolic and ER calcium handling due to hampered ATP fueling of ER calcium pumps. It is concluded that CI dysfunction triggers an adaptive program that depends on extracellular glucose and AMPK-alpha. This response avoids cell death by suppressing energy crisis, oxidative stress induction and substantial mitochondrial depolarization. (C) 2014 Elsevier B.V. All rights reserved.

【 授权许可】

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