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Autophagy is a tightly regulated lysosomal degradation process that mediates the sequestration of intracellular entities to form autophagosomes, and their delivery to lysosomes for bulk degradation [1]. Autophagy plays a key role in the maintenance of cellular homeostasis, in baseline conditions as well as in response to stress. It can function as either a pro-death or pro-survival mechanism in cancer cells, depending on the different stage of tumor development and the cell type [1]. During tumor initiation autophagy has preventive effects; nevertheless once malignant transformation has occurred, autophagy is believed to promote tumor progression, conferring stress resistance and thereby maintaining cancer cell survival [1]. Cellular energetics represents a critical regulatory point for autophagy. Indeed, 5’ adenosine monophosphateactivated protein kinase (AMPK) senses the equilibrium between the phosphorylation status of the adenine nucleotide pool. When equilibrium is shifted to low phosphorylation of nucleotides (especially AMP), AMPK is activated and promotes autophagy to recycle energetic constituents. Mitochondria are a major site of production of higher energy state adenine nucleotide [2]. The high respiratory status of mitochondria allow low AMPK activity, thus maintaining autophagy at low levels [2]. Mitochondria participate in intracellular signaling by different routes. The most characterized sites are the contact sites between mitochondria and endoplasmic reticulum (ER), termed mitochondria-ER associated membranes (MAMs), which provide a platform for the regulation of different processes [3]. This signaling platform participates in the regulation of autophagy. Ca2+ transfer between ER and mitochondria supports mitochondrial respiration and then suppresses autophagy through low AMPK activity [3]. Additionally, the ER-mitochondria interface contributes to autophagosome formation, and proteins localized at MAM compartments are indispensable for proper autophagic vesicle formation [4]. Several oncogenes and oncosuppressors localize at MAMs to regulate communication between organelles and alter cell proliferation or sensitivity to cell death stimuli [3]. Taken together, these observations led us to hypothesize about the possible involvement of promyelocytic leukemia protein (PML) in autophagic process [5]. PML is a tumor suppressor gene that was originally identified at the breakpoint of the t(15;17) translocation of acute promyelocytic leukemia (APL) and is frequently lost or exhibits aberrant expression in human solid tumors and hematopoietic malignancies. We recently identified that PML localizes to the ER and MAMs, where it regulates Ca2+-dependent apoptosis by blocking the activity of IP3R3 and promoting the formation of a multiprotein complex containing IP3R3, AKT and the protein phosphatase PP2a [6]. In our study, we provide evidence that PML at MAMs also plays an essential role Editorial

Novel function of the tumor suppressor PML at ER-mitochondria sites in the control of autophagy