Autophagy as a neuroprotective mechanism against 3-nitropropionic acid-induced cell death

Abstract

The natural environmental toxin 3-Nitropropionic acid (3-NP) is used to induce situations somehow similar to those that take place in human patients suffering the progressive neurodegenerative illness known as Huntington’s disease (HD). Biochemical studies have shown reduced activities of complex II-III in the striatum of human HD brain tissues. 3-NP, structurally similar to succinate, is an inhibitor of succinate dehydrogenases or respiratory complex II. As a consequence, 3-NP stimulates Ca2+ release from mitochondria, decreases mitochondrial membrane potential, induces mitochondrial swelling, stimulates cytochrome c release from mitochondria and leads to a rapid decline of ATP levels. Autophagy, defined as the lysosomal digestion of a cell’s own cytoplasmic material, exerts its functions under conditions that require energy and use of intracellular nutrients. Under these conditions, autophagy shows a rapid increase, permitting the release of substrates used for the maintenance of ATP levels and the new synthesis of proteins that plays a fundamental role in stress adaptation. Autophagy is activated as an adaptive catabolic process in response to different forms of metabolic stress, including ATP depletion, calciumoxidative stress and mitochondrial disruption. Autophagy participates in the turnover of mitochondria, a strictly regulated process called mitophagy. So, autophagy maintaining cell metabolic balance plays an important role in cell fate. Indeed, autophagy is essential for the survival of neurons, since they cannot dilute the level of altered proteins and damaged organelles by means of cell division. We herein summarize and discuss the relevance of intracellular autophagic pathways activated by 3-NP, thus trying to shed light on the potential mechanism underlying the involvement of autophagy in HD model. Finally, we summarize the role of pharmacological modulators in changing 3-NP-induced autophagy and their effects on cell survival.