A Role for Proapoptotic BID in the DNA-Damage Response

SummaryThe BCL-2 family of apoptotic proteins encompasses key regulators proximal to irreversible cell damage. The BH3-only members of this family act as sentinels, interconnecting specific death signals to the core apoptotic pathway. Our previous data demonstrated a role for BH3-only BID in maintaining myeloid homeostasis and suppressing leukemogenesis. In the absence of Bid, mice accumulate chromosomal aberrations and develop a fatal myeloproliferative disorder resembling chronic myelomonocytic leukemia. Here, we describe a role for BID in preserving genomic integrity that places BID at an early point in the path to determine the fate of a cell. We show that BID plays an unexpected role in the intra-S phase checkpoint downstream of DNA damage distinct from its proapoptotic function. We further demonstrate that this role is mediated through BID phosphorylation by the DNA-damage kinase ATM. These results establish a link between proapoptotic Bid and the DNA-damage response

Full Length Bid is sufficient to induce apoptosis of cultured rat hippocampal neurons

BACKGROUND: Bcl-2 homology domain (BH) 3-only proteins are pro-apoptotic proteins of the Bcl-2 family that couple stress signals to the mitochondrial cell death pathways. The BH3-only protein Bid can be activated in response to death receptor activation via caspase 8-mediated cleavage into a truncated protein (tBid), which subsequently translocates to mitochondria and induces the release of cytochrome-C. Using a single-cell imaging approach of Bid cleavage and translocation during apoptosis, we have recently demonstrated that, in contrast to death receptor-induced apoptosis, caspase-independent excitotoxic apoptosis involves a translocation of full length Bid (FL-Bid) from the cytosol to mitochondria. We induced a delayed excitotoxic cell death in cultured rat hippocampal neurons by a 5-min exposure to the glutamate receptor agonist N-methyl-D-aspartate (NMDA; 300 μM). RESULTS: Western blot experiments confirmed a translocation of FL-Bid to the mitochondria during excitotoxic apoptosis that was associated with the release of cytochrome-C from mitochondria. These results were confirmed by immunofluorescence analysis of Bid translocation during excitotoxic cell death using an antibody raised against the amino acids 1–58 of mouse Bid that is not able to detect tBid. Finally, inducible overexpression of FL-Bid or a Bid mutant that can not be cleaved by caspase-8 was sufficient to induce apoptosis in the hippocampal neuron cultures. CONCLUSION: Our data suggest that translocation of FL-Bid is sufficient for the activation of mitochondrial cell death pathways in response to glutamate receptor overactivation

Loss of Muscle MTCH2 Increases Whole-Body Energy Utilization and Protects from Diet-Induced Obesity

SummaryMitochondrial carrier homolog 2 (MTCH2) is a repressor of mitochondrial oxidative phosphorylation (OXPHOS), and its locus is associated with increased BMI in humans. Here, we demonstrate that mice deficient in muscle MTCH2 are protected from diet-induced obesity and hyperinsulinemia and that they demonstrate increased energy expenditure. Deletion of muscle MTCH2 also increases mitochondrial OXPHOS and mass, triggers conversion from glycolytic to oxidative fibers, increases capacity for endurance exercise, and increases heart function. Moreover, metabolic profiling of mice deficient in muscle MTCH2 reveals a preference for carbohydrate utilization and an increase in mitochondria and glycolytic flux in muscles. Thus, MTCH2 is a critical player in muscle biology, modulating metabolism and mitochondria mass as well as impacting whole-body energy homeostasis

Obesity, diabetes and zinc: A workshop promoting knowledge and collaboration between the UK and Israel, November 28–30, 2016 – Israel

Sponsored by the Friends of Israel Educational Foundation (FIEF) and Ben-Gurion University of the Negev and supported by the EU COST action Zinc-Net (COST TD1304), a three-day collaborative UK-Israel workshop was organized by Drs Assaf Rudich, Imre Lengyel and Arie Moran. Participants from the UK and Israel met at the Desert Iris Hotel, Yeruham, Israel between the 28-30th of November 2016 for in-depth discussions, rather than a lecture series, to set the stage for future collaborative grants and projects on diabetes and zinc. Two days of formal scientific sessions with dynamic and wide-ranging discussions was followed by a day of touring and informal networking in the Negev area. This format was previously recognized by our sponsors as both effective and enjoyable and all participants agreed at the end of the meeting that the 3-days provided an excellent basis for future scientific collaboration. The discussions were centered on diabetes and obesity, already at pandemic levels, and zinc homeostasis which is related to the clinical issues and themes of the meeting. The free-flowing discussions were based on short presentations setting the scene for the six main topics: ‘Diabetes and zinc transporters’, ‘Nutrition related factors’, ‘Biomarkers’, ‘Clinical epidemiology’, ‘the Microbiome and diabetes’, and ‘Related diseases’. The abstract style summary of the sessions is followed by the major discussion points raised by the Authors and other participants (UK: Patrik Rorsman, Oxford University; Alan Stewart, University of St Andrews and Israel: Assaf Rudich, Idit Liberty, Rahel Gol, Guy Las and Amos Katz, Ben-Gurion University; Sarah Zangen, Haddassa University). We hope that readers will find this discourse stimulating and some of the ideas might make their way into their research efforts

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field