Response Letter to “Autophagy in Renal Ischemia-Reperfusion Injury: Friend or Foe?”

Abstract

To the Editor: The implications of autophagy in modulating tissue responses during ischemia are far from being elucidated, and Decuypere et al 1 are right to point out that the duration of ischemia could affect the consequences of autophagy on tissue viability and outcomes. The important questions they raise are whether autophagy can directly promote cell dismantlement, and whether this occurs after extended periods of ischemia. They postulate that autophagy is protective in the early times of ischemia, and is destructive when ischemic time is too prolonged; the principle of this “dual role” model is reminiscent of the role of autophagy in cancer, where autophagy carries antioncogenic properties in the early steps of oncogenesis, but is involved in tissue adaptation against stress and fuels cell growth and proliferation in established tumors. To support their model, they refer to the recent description of autosis, a particular type of cell death triggered by autophagy. High concentrations of Tat-Beclin1, a construct that specifically activates autophagy, and by extent, high autophagic flux, promotes autosis. Autosis also occurs in starved HeLa cells, but in a proportion of ≈1% (99% being apoptotic and/or necrotic), and in some dying neurons after 24 h after cerebral hypoxia–ischemia 2. An increased duration of ischemia is not synonymous of increased intensity of autophagy, and, although prolonged ischemia is associated with worse outcomes, it does not mean that these outcomes are a consequence of a submerging autophagic flux, and that cells are directly killed by autophagy. In general, prolonged ischemia (or starvation) is associated with a decrease of autophagic flux rather than an increase for the following reasons: The consumption and depletion of essential autophagic components after long starvation periods, the reactivation of mTOR activity and the inhibition of master regulators of autophagy such as ATG3, AMBRA1 and Beclin1 by caspases, which are activated in response to prolonged stress 3, 4. In some instances autophagy facilitates apoptosis, and autophagy inhibition will result in an increased viability. For example, autophagy degrades the Fap-1 protein phosphatase, a critical negative regulator of apoptotic cell death signaled by the tumor necrosis factor receptor family member, Fas 5. Consequently, inhibition of autophagy would be beneficial for the cell in terms of survival, in part because the apoptotic machinery is down-regulated. Three criteria are needed to be meet for “pure” autophagic cell death: increased autophagic flux, caspase-independent cell death and the reversal of the phenotype with the deletion of autophagy regulators. Whether this occurs after prolonged ischemia in organs such as kidneys remains to be tested and demonstrated. N. Pallet Service de Néphrologie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France Service de Biochimie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France INSERM U1147, Centre Universitaire des Saints Pères, Paris, France Fédération de Recherche C2T2S (Chimie, Toxicologie, Signalisation cellulaire et Cibles Thérapeutiques), Paris, France Université Paris Descartes, Paris, France Sorbonne Paris Cité, Paris, France *Corresponding author: Nicolas Pallet, npallet@yahoo.fr The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.