Project description
Reactive oxygen species in cell differentiation
Reactive oxygen species (ROS) are derivatives of molecular oxygen that are toxic byproducts of metabolism closely associated with oxidative stress. However, low ROS levels produced in mitochondria (mROS) serve as signals for normal biological processes. The MitoSignal project, funded by the European Research Council, will investigate how mROS drive cell differentiation. Researchers will use Trypanosoma parasites – the causative agents of sleeping sickness – as a simple model organism containing a single mitochondrion that undergoes various metabolic changes during programmed development. MitoSignal results will provide important insights into the interplay between mitochondria and the rest of the cell in cell fate decisions.
Objective
Mitochondria perform three essential functions: ATP production, metabolite synthesis and cellular signaling. These signals, communicating the bioenergetic and biosynthetic fitness of the organelle to the nucleus, play a powerful role in determining cellular fate. The incorporation of mitochondrial reactive oxygen species (mROS) in cellular signaling is an interesting evolutionary outcome, as excess levels of these potent oxidizers have been implicated in many pathologies. While most research focuses on these outcomes of oxidative stress, much less is known about how mROS drive a range of physiological responses. Furthermore, the available studies are limited to a few traditional model organisms, featuring complex cellular systems with numerous mitochondria at different energetic states. Here, we propose to utilize the unicellular parasites, Trypanosoma brucei and T. congolense, as simplified but elegant models to define mROS-driven cellular differentiation. As these protists undergo programmed development between several distinct life cycle forms, there are striking changes to the structure and physiology of their single mitochondrion that manifest in elevated ROS levels. Importantly, we demonstrated that these ROS molecules are essential for the developmental progression of the parasite. Employing these well-chosen models and combining next-generation biosensors, advanced bioenergetic methods, redox proteomics and a CRISPR/Cas9 genetic screen, we will answer the following fundamental questions: Does mROS drive Trypanosoma cellular differentiation? What molecular processes are responsible for the elevated mROS levels during differentiation? How is the redox signal propagated to the rest of the cell? The proposed research aspires to unravel the fundamental mechanisms underlying the intricate communication between mitochondria and the rest of the cell, featuring cellular hallmarks of cell fate decisions.
Fields of science
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensorsbiosensors
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesbasic medicinepathology
- medical and health sciencesbasic medicinephysiology
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
ERC - Support for frontier research (ERC)Host institution
370 05 Ceske Budejovice
Czechia