ATP-driven and AMPK-independent autophagy in an early branching eukaryotic parasite

Abstract

Autophagy is a catabolic cellular process required to maintain protein synthesis, energy production and other essential activities in starved cells. While the exact nutrient sensor(s) is yet to be identified, deprivation of amino acids, glucose, growth factor and other nutrients can serve as metabolic stimuli to initiate autophagy in higher eukaryotes. In the early-branching unicellular parasite Trypanosoma brucei, which can proliferate as procyclic form (PCF) in the tsetse fly or as bloodstream form (BSF) in animal hosts, autophagy is robustly triggered by amino acid deficiency but not by glucose depletion. Taking advantage of the clearly defined adenosine triphosphate (ATP) production pathways in T. brucei, we have shown that autophagic activity depends on the levels of cellular ATP production, using either glucose or proline as a carbon source. While autophagosome formation positively correlates with cellular ATP levels; perturbation of ATP production by removing carbon sources or genetic silencing of enzymes involved in ATP generation pathways, also inhibited autophagy. This obligate energy dependence and the lack of glucose starvation-induced autophagy in T. brucei may reflect an adaptation to its specialized, parasitic life style.

Cell-based and multi-omics profiling reveals dynamic metabolic repurposing of mitochondria to drive developmental progression of Trypanosoma brucei

“…Among the most striking alterations was an accumulation of several TCA cycle intermediates including malate and citrate (Fig 9E). Interestingly, the molecules crucial for energy storage, unusually high levels, as also reported elsewhere [44]. The measured values are shown in S1 Data (means ± SD, n = 6-10, �� P < 0.01).…”

Calcium-sensitive pyruvate dehydrogenase phosphatase is required for energy metabolism, growth, differentiation, and infectivity of Trypanosoma cruzi

“…The increase in the AMP/ATP ratio produced by down-regulation of the TCA cycle could promote autophagy by stimulation of AMP-dependent kinase (AMPK) (65). However, this correlation was not previously observed in T. cruzi when characterizing MCU and MCUb subunits of the MCU complex (38), suggesting an AMPK-independent autophagy pathway similar to that of T. brucei (66). Further studies should be performed to elucidate the mechanism of autophagy induction in T. cruzi.…”

The Uptake and Metabolism of Amino Acids, and Their Unique Role in the Biology of Pathogenic Trypanosomatids

“…Conversely, among the amino acids are not only those that protect against autophagy, but also ones that, by the trypanosome’s starvation for them, induce the process, similarly to what has been reported for other eukaryotes. For example, He and collaborators described that amino acid starvation can trigger autophagy independently of the AMP-activated-Protein-Kinase-mediated energy sensing mechanisms [ 317 , 318 ]. Further studies are required to unravel the details of the pathways involved.…”