2. Academic Validation
  3. Mutations in NDUFS1 Cause Metabolic Reprogramming and Disruption of the Electron Transfer

Mutations in NDUFS1 Cause Metabolic Reprogramming and Disruption of the Electron Transfer

  • Cells. 2019 Sep 25;8(10):1149. doi: 10.3390/cells8101149.
Yang Ni 1 2 3,  Muhammad A Hagras 4 5,  Vassiliki Konstantopoulou 6,  Johannes A Mayr 7,  Alexei A Stuchebrukhov 4,  David Meierhofer 8
Affiliations

Affiliations

  • 1 Mass Spectrometry Facility, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 2 Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
  • 3 Present address: Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, 3000 Leuven, Belgium.
  • 4 Department of Chemistry, University of California Davis, Davis, CA 95616, USA.
  • 5 Present address: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 6 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria.
  • 7 Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
  • 8 Mass Spectrometry Facility, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. [email protected].
PMID: 31557978 DOI: 10.3390/cells8101149
Abstract

Complex I (CI) is the first Enzyme of the mitochondrial respiratory chain and couples the electron transfer with proton pumping. Mutations in genes encoding CI subunits can frequently cause inborn metabolic errors. We applied proteome and metabolome profiling of patient-derived cells harboring pathogenic mutations in two distinct CI genes to elucidate underlying pathomechanisms on the molecular level. Our results indicated that the electron transfer within CI was interrupted in both patients by different mechanisms. We showed that the biallelic mutations in NDUFS1 led to a decreased stability of the entire N-module of CI and disrupted the electron transfer between two iron-sulfur clusters. Strikingly interesting and in contrast to the proteome, metabolome profiling illustrated that the pattern of dysregulated metabolites was almost identical in both patients, such as the inhibitory feedback on the TCA cycle and altered glutathione levels, indicative for Reactive Oxygen Species (ROS) stress. Our findings deciphered pathological mechanisms of CI deficiency to better understand inborn metabolic errors.

Keywords

complex I (CI) deficiency; electron tunneling (ET); metabolome and proteome profiling; reactive oxygen species (ROS); respirasome assembly.

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