The term “mitochondrial permeability transition” (MPT) refers to an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes. Due to osmotic forces, M...

Promoting Apoptosis: During acute disease, the promyelocytic leukemia (PML) protein becomes fused to another protein as a result of a chromosomal translocation. This protein appears to have multiple and varied functions, including the ability to form distinctive complexes in the nucleus that suppress tumorigenesis and promote apoptotic cell death. Giorgi et al. (p. 1247 , published online 28 October; see the Perspective by Culjkovic-Kraljacic and Borden ) have proposed a mechanism by which PML influences the cellular signals that promote apoptosis. The protein was localized at sites of contact between the endoplasmic reticulum and mitochondria, where it associated with a calcium channel, a protein kinase, and a protein phosphatase, to regulate calcium mobilization into the mitochondrion, which then triggers the cell death program.

The pro-oncogenic transcription factor STAT3 is constitutively activated in a wide variety of tumours that often become addicted to its activity, but no unifying view of a core function determining this widespread STAT3-dependence has yet emerged. We show here that constitutively active STAT3 acts as a master regulator of cell metabolism, inducing aerobic glycolysis and down-regulating mitochondrial activity both in primary fibroblasts and in STAT3-dependent tumour cell lines. As a result, cells are protected from apoptosis and senescence while becoming highly sensitive to glucose deprivation. We show that enhanced glycolysis is dependent on HIF-1α up-regulation, while reduced mitochondrial activity is HIF-1α-independent and likely caused by STAT3-mediated down-regulation of mitochondrial proteins. The induction of aerobic glycolysis is an important component of STAT3 pro-oncogenic activities, since inhibition of STAT3 tyrosine phosphorylation in the tumour cell lines down-regulates glycolysis prior to leading to growth arrest and cell death, both in vitro and in vivo. We propose that this novel, central metabolic role is at the core of the addiction for STAT3 shown by so many biologically different tumours.