ER-PM contacts in nonclathrin endocytosis: The epidermal growth factor receptor (EGFR) is internalized through both clathrin-mediated endocytosis and nonclathrin endocytosis (NCE). The two pathways act in concert to sustain EGFR signaling or its long-term attenuation. The mechanistic underpinnings of EGFR-NCE are unclear. Caldieri et al. used a variety of cell and molecular biology approaches to identify nine regulators of EGFR-NCE (see the Perspective by Tan and Anderson). They also identified an additional cargo of the pathway (CD147). One of the regulators of the pathway was the endoplasmic reticulum (ER)-resident protein reticulon 3 (RTN3). Unexpectedly, EGFR-NCE required the formation of specific contacts between the plasma membrane (PM) and the cortical ER, mediated by RTN3. ER-PM contact sites were required in the very early steps of the internalization process for the maturation of NCE tubular intermediates. Science , this issue p. 617 ; see also p. 584

Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca²⁺, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation.

Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes.