Cell-based and multi-omics profiling reveals dynamic metabolic repurposing of mitochondria to drive developmental progression of Trypanosoma brucei
Abstract Mitochondrial metabolic remodeling is a hallmark of the Trypanosoma brucei digenetic life cycle because the insect stage utilizes a cost-effective oxidative phosphorylation (OxPhos) to generate ATP, while bloodstream cells switch to aerobic glycolysis. Due to difficulties in acquiring enough parasites from the tsetse fly vector, the dynamics of the parasite’s metabolic rewiring in the vector have remained obscure. Here, we took advantage of in vitro–induced differentiation to follow changes at the RNA, protein, and metabolite levels. This multi-omics and cell-based profiling showed an immediate redirection of electron flow from the cytochrome-mediated pathway to an alternative oxidase (AOX), an increase in proline consumption, elevated activity of complex II, and certain tricarboxylic acid (TCA) cycle enzymes, which led to mitochondrial membrane hyperpolarization and increased reactive oxygen species (ROS) levels. Interestingly, these ROS molecules appear to act as signaling molecules driving developmental progression because ectopic expression of catalase, a ROS scavenger, halted the in vitro–induced differentiation. Our results provide insights into the mechanisms of the parasite’s mitochondrial rewiring and reinforce the emerging concept that mitochondria act as signaling organelles through release of ROS to drive cellular differentiation.
Introduction:
In most eukaryotic cells, energy metabolism is an interplay between two energy production pathways to generate ATP: an efficient mitochondrial oxidative phosphorylation (OxPhos) and an ancient glycolytic pathway. A “textbook-like” aerobic eukaryotic cell relies mainly on cost-effective OxPhos to fulfill cellular requirements for ATP. Exceptions apply to some rapidly proliferating cells, e.g., some cancer cells exploit high rates of fermentative glycolysis, irrespective of oxygen availability [1]. Oncogenic metabolic reprogramming from OxPhos to glycolysis allows the malignant cell to fulfill a great demand for synthesis of nucleotides and amino acids, the building blocks of DNA and proteins, respectively, to promote tumor growth and progression [2]. Metabolic rewiring to aerobic glycolysis also drives the activation of macrophages to a pro-inflammatory phenotype in response to infection. This phenotypic switch involves suppressed OxPhos, disruption of the tricarboxylic acid (TCA) cycle, reactive oxygen species (ROS) production, and accumulation of succinate [3]. The factors that underlie the striking metabolic changes during the aforementioned cellular processes are not fully understood. However, multiple lines of evidence implicate alterations in mitochondrial function that lead to the release of signal molecules to drive cell differentiation. Prominent examples of these signals are ROS and certain metabolic intermediates (e.g., succinate, citrate, and itaconate) with the ability to affect gene expression at the global level via posttranslational mechanisms [4–6]. This demonstrates how mitochondrial plasticity and metabolic remodeling are crucial for cells to respond to various signals to acquire new functions.
Doleželová E., Kunzová M., Dejung M., Levin M., Panicucci B., Regnault C., Janzen C.J., Barrett M.P., Butter F., Zíková A. 2020: Cell-based and multi-omics profiling reveals dynamic metabolic repurposing of mitochondria to drive developmental progression of Trypanosoma brucei. PloS Biology (in press). [IF=8.386]
DOI: 10.1371/journal.pbio.3000741
