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Targeting a major hub of cell fate decisions – the mitochondrial-associated membrane
William L. Carroll and Nikki A. Evensen
Departments of Pediatrics and Pathology, Perlmutter Cancer Center, NYU-Langone Medical Center, New York, NY, USA E-mail: WILLIAM L. CARROLL - william.carroll@nyumc.org
doi:10.3324/haematol.2018.208355
Great progress has been made in the treatment of human cancer but, unfortunately, there remains an abundance of treatment failures due to pri- mary therapy resistance and/or the emergence of drug refractory clones. This is certainly true for acute leukemias, which are the most common malignancies in children and while they make up a smaller fraction of cancer in adults, their impact is substantial given the poorer outcome. Furthermore, the high doses of cytotox- ic agents that are often used in therapy are associated with short- and long-term side effects. Thus, there is an urgent need to develop novel therapeutic approaches to improve outcome and decrease side effects. One such strategy, taken by Koczian and colleagues and described in this issue of Haematologica, is to augment the effective- ness of conventional agents.1 They report that the use of the small molecule inhibitor of protein disulfide iso- merase (PDI), PS89, has a significant impact on the effec- tiveness of cytostatic agents used routinely in the therapy of acute leukemias. The model that emerges is that PS89 amplifies the apoptotic stimulus induced by cytotoxic therapy, thereby allowing for increased efficacy at lower doses, through modulation of proteins at the mitochondr- ial-endoplasmic reticulum (ER) interface. The agent itself has poor pharmacokinetic properties limiting in vivo examination, but the results indicate substantial benefit and a wide therapeutic index. Much work remains to be done but the results emphasize the opportunity to target
a unique intracellular sub-compartment that plays a key role in cell fate decisions: the interface between the ER and mitochondria.
Mitochondria are multifaceted organelles responsible for an array of cell functions critical for energy produc- tion, redox balance, adaptation to cell stress, and activa- tion of the intrinsic apoptotic pathway. They make up 20% of the cytoplasmic volume of a cell and are dynamic, motile structures constantly altering shape through fis- sion and fusion. These alterations involve two lipid bilay- ers that make up the inner membrane forming cristae (containing membrane-bound enzymes involved in oxidative phosphorylation) which enclose the matrix, and the smooth outer membrane. Mitochondria make important contact with other organelles, particularly the ER, which is in direct contacts with 20% of the mito- chondrial surface. Changes in energy metabolism related to cancer, the so-called Warburg effect, have received renewed interest, especially with the discovery of “onco- metabolites”, but changes that occur at the mitochondri- al-ER interface are also critical in controlling mitochondr- ial metabolism and cell fate decisions.2
The mitochondrial-ER interface, commonly referred to as the mitochondria-associated membrane (MAM), is a proteinaceous tether facilitating bidirectional communi- cation between the two organelles controlling the balance between survival and death.3,4 The exchange of metabo- lites and contact at the interface controls energy produc-
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