Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1528-7) contains supplementary material, which is available to authorized users.
Highlights
Abbreviations AD Alzheimer’s dementia Amyotrophic Lateral Sclerosis (ALS) Amyotrophic lateral sclerosis amyloid precursor protein (APP) Amyloid precursor protein ATG Autophagy-related ATL1/3 Atlastin 1/3 CMT Charcot–Marie–Tooth disease CNX Calnexin double FYVE-containing protein 1 (DFCP1) Double FYVE-containing protein 1 DJ-1 Protein deglycase DJ-1 Drp1 Dynamin-related protein 1 ER membrane protein complex (EMC) Endoplasmic reticulum membrane complex endoplasmic reticulum (ER) Endoplasmic reticulum ER-Mitochondria Encounter Structure (ERMES) Endoplasmic reticulum-mitochondria encounter structure familial AD (FAD) Familial Alzheimer’s dementia focused ion beam scanning electron microscopy (FIB-SEM) Focused ion beam scanning electron
We focus this review on the contact sites that are formed between mitochondria and a specialized subdomain of the endoplasmic reticulum (ER) termed MitochondriaAssociated Membranes (MAMs)
Many questions remain as to how ER-mitochondria membrane contact sites (MCSs) are maintained and regulated, it is clear that many different pathways intertwine at these signaling hubs
Summary
The MAM fraction can be detached from mitochondria through proteolysis with trypsin or Proteinase K, showing that a proteinaceous tether is responsible for connecting both membranes [26] The presence of such a protein bridge has been confirmed in electron microscopy studies [26, 97], but despite this, the identity of its components still remains largely elusive. Genetic screens independently led to the discovery of the ER-Mitochondria Encounter Structure (ERMES) complex [55] and the ER membrane protein complex (EMC) [60] as functional tethers between the ER and mitochondria (see Fig. 2 lower part). By automated serial block face imaging, large image stacks are generated at high resolution, allowing precise 3D reconstruction of a large cellular volume In this dataset, over 600 10 nm z-slices were obtained resulting in a 3D dataset at 5 × 5 × 10 nm voxels.
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