title: Autophagy and phagocytosis-like cell cannibalism exert opposing effects on cellular survival during metabolic stress.
abstract: Understanding mechanisms controlling neuronal cell death and survival under conditions of altered energy supply (e.g., during stroke) is fundamentally important for the development of therapeutic strategies. The function of autophagy herein is unclear, as both its beneficial and detrimental roles have been described. We previously demonstrated that loss of AMP-activated protein kinase (AMPK), an evolutionarily conserved enzyme that maintains cellular energy balance, leads to activity-dependent degeneration in neuronal tissue. Here, we show that energy depletion in Drosophila AMPK mutants results in increased autophagy that convincingly promotes, rather than rescues, neurodegeneration. The generated excessive autophagic response is accompanied by increased TOR and S6K activity in the absence of an AMPK-mediated negative regulatory feedback loop. Moreover, energy-depleted neurons use a phagocytic-like process as a means to cellular survival at the expense of surrounding cells. Consequently, phagocytosis stimulation by expression of the scavenger receptor Croquemort significantly delays neurodegeneration. This study thus reveals a potentially novel strategy for cellular survival during conditions of extreme energy depletion, resembling xeno-cannibalistic events seen in metastatic tumors. We provide new insights into the roles of autophagy and phagocytosis in the neuronal metabolic stress response and open new avenues into understanding of human disease and development of therapeutic strategies.
authors.affiliation: Laboratory of Behavioral and Developmental Genetics, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Poels
authors.forename: M R
authors.initials: MR
authors.lastname: Spasić
authors.forename: M
authors.initials: M
authors.lastname: Gistelinck
authors.forename: J
authors.initials: J
authors.lastname: Mutert
authors.forename: A
authors.initials: A
authors.lastname: Schellens
authors.forename: P
authors.initials: P
authors.lastname: Callaerts
authors.forename: K K
authors.initials: KK
authors.lastname: Norga
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D057899:Cytophagocytosis / Q000187:drug effects*; D004330:Drosophila / Q000201:enzymology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D018021:Lithium Chloride / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D018021:Lithium Chloride