Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-α
Biochimica et Biophysica Acta - Molecular Basis of Disease , Volume 1852 - Issue 3 p. 529- 540
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-α/SIRT1/mTOR levels. Survival of CI-inhibited cells was strictly glucose-dependent and accompanied by increased AMPK-α phosphorylation, which occurred without changes in ATP or cytosolic calcium levels. Conversely, cells devoid of AMPK-α 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-α. This response avoids cell death by suppressing energy crisis, oxidative stress induction and substantial mitochondrial depolarization.
|Calcium homeostasis, Glycolysis, Metabolic regulation, Mitochondrial dynamics, Redox signaling, Respirometry|
|Biochimica et Biophysica Acta - Molecular Basis of Disease|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Distelmaier, F, Valsecchi, F, Liemburg-Apers, D.C, Lebiedzinska, M, Rodenburg, R.J.T, Heil, S.G, … Koopman, W.J.H. (2015). Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-α. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1852(3), 529–540. doi:10.1016/j.bbadis.2014.12.012