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Nature communications
06 07, 2018;9 (1): 2221.

Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints.

Ayenachew Bezawork-Geleta, He Wen, LanFeng Dong, Bing Yan, Jelena Vider, Stepana Boukalova, Linda Krobova, Katerina Vanova, Renata Zobalova, Margarita Sobol, Pavel Hozak, Silvia Magalhaes Novais, Veronika Caisova, Pavel Abaffy, Ravindra Naraine, Ying Pang, Thiri Zaw, Ping Zhang, Radek Sindelka, Mikael Kubista, Steven Zuryn, Mark P Molloy, Michael V Berridge, Karel Pacak, Jakub Rohlena, Sunghyouk Park, Jiri Neuzil
Author Information
  1. Ayenachew Bezawork-Geleta: School of Medical Sciences, Griffith University, Southport, 4222, Qld, Australia. a.bezawork-geleta@griffith.edu.au.
  2. He Wen: Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518060, China.
  3. LanFeng Dong: School of Medical Sciences, Griffith University, Southport, 4222, Qld, Australia.
  4. Bing Yan: School of Medical Sciences, Griffith University, Southport, 4222, Qld, Australia.
  5. Jelena Vider: School of Medical Sciences, Griffith University, Southport, 4222, Qld, Australia. ORCID
  6. Stepana Boukalova: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic.
  7. Linda Krobova: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic.
  8. Katerina Vanova: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic.
  9. Renata Zobalova: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic.
  10. Margarita Sobol: Institute of Molecular Genetics, Czech Academy of Sciences, Prague, 14220, Czech Republic.
  11. Pavel Hozak: Institute of Molecular Genetics, Czech Academy of Sciences, Prague, 14220, Czech Republic.
  12. Silvia Magalhaes Novais: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic.
  13. Veronika Caisova: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA.
  14. Pavel Abaffy: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic.
  15. Ravindra Naraine: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic.
  16. Ying Pang: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA.
  17. Thiri Zaw: Australian Proteome Analysis Facility, Macquarie University, North Ryde, 2109, NSW, Australia.
  18. Ping Zhang: School of Medical Sciences, Griffith University, Southport, 4222, Qld, Australia.
  19. Radek Sindelka: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic.
  20. Mikael Kubista: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic.
  21. Steven Zuryn: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, 4072, Qld, Australia.
  22. Mark P Molloy: Australian Proteome Analysis Facility, Macquarie University, North Ryde, 2109, NSW, Australia.
  23. Michael V Berridge: Malaghan Institute of Medical Research, Wellington, 6242, New Zealand.
  24. Karel Pacak: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA.
  25. Jakub Rohlena: Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 25250, Czech Republic. jakub.rohlena@ibt.cas.cz.
  26. Sunghyouk Park: College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul, 08826, Korea. psh@snu.ac.kr.
  27. Jiri Neuzil: School of Medical Sciences, Griffith University, Southport, 4222, Qld, Australia. j.neuzil@griffith.edu.au.
PMID: 29880867 DOI: 10.1038/s41467-018-04603-z

Abstract

Cell growth and survival depend on a delicate balance between energy production and synthesis of metabolites. Here, we provide evidence that an alternative mitochondrial complex II (CII) assembly, designated as CII, serves as a checkpoint for metabolite biosynthesis under bioenergetic stress, with cells suppressing their energy utilization by modulating DNA synthesis and cell cycle progression. Depletion of CII leads to an imbalance in energy utilization and metabolite synthesis, as evidenced by recovery of the de novo pyrimidine pathway and unlocking cell cycle arrest from the S-phase. In vitro experiments are further corroborated by analysis of paraganglioma tissues from patients with sporadic, SDHA and SDHB mutations. These findings suggest that CII is a core complex inside mitochondria that provides homeostatic control of cellular metabolism depending on the availability of energy.

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MeSH Term

Animals
Biosynthetic Pathways
Cell Line, Tumor
Electron Transport Complex II
Energy Metabolism
Gene Knockout Techniques
HEK293 Cells
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Mitochondria
Mutation
Paraganglioma
RNA, Small Interfering
S Phase Cell Cycle Checkpoints
Stress, Physiological
Succinate Dehydrogenase
Xenograft Model Antitumor Assays

Chemicals

RNA, Small Interfering
respiratory complex II
Electron Transport Complex II
SDHA protein, human
SDHB protein, human
Succinate Dehydrogenase
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 39

Word Cloud

Created with Highcharts 10.0.0energyCIIsynthesiscomplexIIassemblymetabolitestressutilizationcellcycleCellgrowthsurvivaldependdelicatebalanceproductionmetabolitesprovideevidencealternativemitochondrialdesignatedservescheckpointbiosynthesisbioenergeticcellssuppressingmodulatingDNAprogressionDepletionleadsimbalanceevidencedrecoverydenovopyrimidinepathwayunlockingarrestS-phasevitroexperimentscorroboratedanalysisparagangliomatissuespatientssporadicSDHASDHBmutationsfindingssuggestcoreinsidemitochondriaprovideshomeostaticcontrolcellularmetabolismdependingavailabilityAlternativerespiratoryconnectsmetaboliccheckpoints

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