Cover illustration The cover image is taken from the article “The high‐resolution X‐ray structure of vinca‐domain inhibitors of microtubules provides a rational approach for drug design” by W. Chengyong et al. (pp. 195–205).

Mitochondria contain more than 1000 different proteins, including several proteolytic enzymes. These mitochondrial proteases form a complex system that performs limited and terminal proteolysis to build the mitochondrial proteome, maintain and control its functions or degrade mitochondrial proteins and peptides. During protein biogenesis presequence proteases cleave and degrade mitochondrial targeting signals to obtain mature functional proteins. Processing by proteases also exerts a regulatory role in modulation of mitochondrial functions and quality control enzymes degrade misfolded, aged or superfluous proteins. Depending on their different functions and substrates, defects in mitochondrial proteases can affect the majority of the mitochondrial proteome or only a single protein. Consequently, mutations in mitochondrial proteases have been linked to several human diseases. This review gives an overview of the components and functions of the mitochondrial proteolytic machinery and highlights the pathological consequences of dysfunctional mitochondrial protein processing and turnover.

The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain‐containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 co‐precipitates with, and is directly phosphorylated by, mTOR. Using a phospho‐specific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2‐mediated phosphorylation in a growth factor‐dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor‐ and amino acid‐sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.

Cover illustration GPCRs and heterotrimeric G Proteins define the Hallmarks of Cancer. They act as cancer drivers by dysregulating oncocrine cellular signalling networks within and outside the tumor microenvironment. GPCR is schematized in pink, heterotrimeric G proteins in blue (Ga) and green (Gbg), the membrane in pale orange. Figure adapted from Hanahan and Weinberg, Cell, 2011 and modified from SMART (Servier Medical Art), licensed under a CC BY 3.0, and taken from “G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers” by N. Arang and J.S. Gutkind (pp. 4201–4232).