Mitochondria-associated membranes as hubs for neurodegeneration.

There is a growing appreciation that membrane-bound organelles in eukaryotic cells communicate directly with one another through direct membrane contact sites. Mitochondria-associated membranes are specialized subdomains of the endoplasmic reticulum that function as membrane contact sites between the endoplasmic reticulum and mitochondria. These sites have emerged as major players in lipid metabolism and calcium signaling. More recently also autophagy and mitochondrial dynamics have been found to be regulated at ER-mitochondria contact sites. Neurons critically depend on mitochondria-associated membranes as a means to exchange metabolites and signaling molecules between these organelles. This is underscored by the fact that genes affecting mitochondrial and endoplasmic reticulum homeostasis are clearly overrepresented in several hereditary neurodegenerative disorders. Conversely, the processes affected by the contact sites between the endoplasmic reticulum and mitochondria are widely implicated in neurodegeneration. This review will focus on the most recent data addressing the structural composition and function of the mitochondria-associated membranes. In addition, the 3D morphology of the contact sites as observed using volume electron microscopy is discussed. Finally, it will highlight the role of several key proteins associated with these contact sites that are involved not only in dementias, amyotrophic lateral sclerosis and Parkinson's disease, but also in axonopathies such as hereditary spastic paraplegia and Charcot-Marie-Tooth disease.

Transport by circulating myeloid cells drives liposomal accumulation in inflamed synovium.

The therapeutic potential of liposomes to deliver drugs into inflamed tissue is well documented. Liposomes are believed to largely transport drugs into inflamed joints by selective extravasation through endothelial gaps at the inflammatory sites, known as the enhanced permeation and retention effect. However, the potential of blood-circulating myeloid cells for the uptake and delivery of liposomes has been largely overlooked. Here we show that myeloid cells can transport liposomes to inflammatory sites in a collagen-induced arthritis model. It is shown that the selective depletion of the circulating myeloid cells reduces the accumulation of liposomes up to 50-60%, suggesting that myeloid-cell-mediated transport accounts for more than half of liposomal accumulation in inflamed regions. Although it is widely believed that PEGylation inhibits premature liposome clearance by the mononuclear phagocytic system, our data show that the long blood circulation times of PEGylated liposomes rather favours uptake by myeloid cells. This challenges the prevailing theory that synovial liposomal accumulation is primarily due to the enhanced permeation and retention effect and highlights the potential for other pathways of delivery in inflammatory diseases.

Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.

Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors. While chaperones of the mitochondrial matrix are well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. Here we show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. Protein misfolding in the mitochondrial intermembrane space leads to increased recruitment of small heat shock proteins. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration, while aggregation of aggregation-prone substrates is countered in their presence. Charcot-Marie-Tooth disease-causing mutations disturb the mitochondrial function of HSPB1, potentially linking previously observed mitochondrial dysfunction in Charcot-Marie-Tooth type 2F to its role in the mitochondrial intermembrane space. Our results reveal that small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space.