Hormesis enables cells to handle accumulating toxic metabolites during increased energy flux
Johanna Zemva,
Christoph Andreas Fink,
Thomas Henry Fleming,
Leonard Schmidt,
Anne Loft,
Stephan Herzig,
Robert André Knieß,
Matthias Mayer,
Bernd Bukau,
Peter Paul Nawroth,
Jens Tyedmers
Affiliations
Johanna Zemva
Department for Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Christoph Andreas Fink
Department for Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Thomas Henry Fleming
Department for Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Leonard Schmidt
Department for Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Anne Loft
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg and Joint Heidelberg-IDC Translational Diabetes Program, Department for Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Stephan Herzig
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg and Joint Heidelberg-IDC Translational Diabetes Program, Department for Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Robert André Knieß
Center for Molecular Biology of Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
Matthias Mayer
Center for Molecular Biology of Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
Bernd Bukau
Center for Molecular Biology of Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
Peter Paul Nawroth
Department for Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Jens Tyedmers
Department for Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Energy production is inevitably linked to the generation of toxic metabolites, such as reactive oxygen and carbonyl species, known as major contributors to ageing and degenerative diseases. It remains unclear how cells can adapt to elevated energy flux accompanied by accumulating harmful by-products without taking any damage. Therefore, effects of a sudden rise in glucose concentrations were studied in yeast cells. This revealed a feedback mechanism initiated by the reactive dicarbonyl methylglyoxal, which is formed non-enzymatically during glycolysis. Low levels of methylglyoxal activate a multi-layered defence response against toxic metabolites composed of prevention, detoxification and damage remission. The latter is mediated by the protein quality control system and requires inducible Hsp70 and Btn2, the aggregase that sequesters misfolded proteins. This glycohormetic mechanism enables cells to pre-adapt to rising energy flux and directly links metabolic to proteotoxic stress. Further data suggest the existence of a similar response in endothelial cells.
