RESUMO
Autophagy plays an important role in cellular survival by resupplying cells with nutrients during starvation or by clearing misfolded proteins and damaged organelles and thereby preventing degenerative diseases. Conversely, the autophagic process is also recognized as a cellular death mechanism. The circumstances that determine whether autophagy has a beneficial or a detrimental role in cellular survival are currently unclear. We recently showed that autophagy induction is detrimental in neurons that lack a functional AMPK enzyme (AMP-activated protein kinase) and that suffer from severe metabolic stress. We further demonstrated that autophagy and AMPK are interconnected in a negative feedback loop that prevents excessive and destructive stimulation of the autophagic process. Finally, we uncovered a new survival mechanism in AMPK-deficient neurons--cell cannibalism.
Assuntos
Autofagia , Citofagocitose , Neurônios/citologia , Proteínas Quinases Ativadas por AMP/deficiência , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Sobrevivência Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/enzimologia , Neurônios/enzimologia , Células Fotorreceptoras de Invertebrados/citologia , Células Fotorreceptoras de Invertebrados/enzimologia , Estresse FisiológicoRESUMO
AMP-activated protein kinase (AMPK) is an evolutionarily conserved cellular switch that activates catabolic pathways and turns off anabolic processes. In this way, AMPK activation can restore the perturbation of cellular energy levels. In physiological situations, AMPK senses energy deficiency (in the form of an increased AMP/ATP ratio), but it is also activated by metabolic insults, such as glucose or oxygen deprivation. Metformin, one of the most widely prescribed anti-diabetic drugs, exerts its actions by AMPK activation. However, while the functions of AMPK as a metabolic regulator are fairly well understood, its actions in neuronal cells only recently gained attention. This review will discuss newly emerged functions of AMPK in neuroprotection and neurodegeneration. Additionally, recent views on the role of AMPK in autophagy, an important catabolic process that is also involved in neurodegeneration and cancer, will be highlighted.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Sobrevivência Celular , Neurônios/citologia , Neurônios/enzimologia , Proteínas Quinases Ativadas por AMP/química , Proteínas Quinases Ativadas por AMP/genética , Animais , Evolução Molecular , Humanos , Transdução de SinaisRESUMO
AMP-activated protein kinase (AMPK) constitutes a molecular hub for cellular metabolic control, common to all eukaryotic cells. Numerous reports have established how AMPK responds to changes in the AMP:ATP ratio as a measure of cellular energy levels. In this way, it integrates control over a number of metabolic enzymes and adapts cellular processes to the current energy status in various cell types, such as muscle and liver cells. The role of AMPK in the development, function, and maintenance of the nervous system, on the other hand, has only recently gained attention. Neurons, while highly metabolically active, have poor capacity for nutrient storage and are thus sensitive to energy fluctuations. Recent reports demonstrate that AMPK may have neuroprotective properties and is activated in neurons by resveratrol but also by metabolic stress in the form of ischemia/hypoxia and glucose deprivation. Novel studies on AMPK also implicate neuronal activity as a critical factor in neurodegeneration. Here we discuss the latest advances in the knowledge of AMPK's role in the metabolic control and survival of excitable cells.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Encéfalo/enzimologia , Metabolismo Energético/fisiologia , Neurônios/enzimologia , Animais , Química Encefálica , Sobrevivência Celular/fisiologia , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Humanos , Hipóxia-Isquemia Encefálica/enzimologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Estresse Fisiológico/fisiologiaRESUMO
Exploring mechanisms that govern neuronal responses to metabolic stress is essential for the development of therapeutic strategies aimed at treatment of neuronal injury and disease. AMP-activated protein kinase (AMPK) is a key enzyme regulating cellular energy homeostasis that responds to changes in cellular energy levels by promoting energy-restorative and inhibiting energy-consumptive processes. Recent studies have suggested that AMPK might have a neuroprotective function. However, the existing evidence is contradictory and almost exclusively derived from in vitro studies based on drug treatments and metabolic stress models. To tackle these issues in vivo, we used the Drosophila visual system. In this report, we describe a novel Drosophila mutant, alicorn (alc), encoding the single beta regulatory subunit of AMPK. Loss of alc using the eyFlp system causes severe early-onset progressive nonapoptotic neurodegeneration in the retina, the optic lobe, and the antennae, as well as behavioral and neurophysiological defects. Retinal degeneration occurs immediately after normal neuronal differentiation, can be enhanced by exposure to light, and can be prevented by blocking photoreceptor excitation. Furthermore, AMPK is required for proper viability of differentiated photoreceptors by mechanisms unrelated to polarity events that AMPK controls in epithelial tissues. In conclusion, AMPK does not affect photoreceptor development but is crucial to maintaining integrity of mature neurons under conditions of increased activity and provides protection from excitotoxicity.