Mitochondria-associated membranes as hubs for neurodegeneration

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.

Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

“…The molecular mechanism underlying the physiopathology of AD is rather unclear, but AD has interestingly been associated with altered metabolism, altered Ca 2+ homeostasis and mitochondrial dysfunction. Consistent with these alterations, several evidence suggested that MAMs may play a role in neurodegenerative diseases, including AD, as recently highlighted by several reviews (Volgyi et al 2015, Area-Gomez & Schon 2016, Joshi et al 2016, Krols et al 2016, Paillusson et al 2016. Indeed, presenilins are enriched at MAM (Area-Gomez et al 2009).…”

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration

“…Our assay monitors overall IP 3 -induced calcium release into the cytoplasm through IP 3 R1, 2 and 3 (Figure 6E); the observed reduction in cytoplasmic calcium release may be associated with localized, increased calcium flux at mitochondrial associated membranes where IP 3 R1 is clustered (Krols et al, 2016; Raturi and Simmen, 2013). Alternatively, early increases in calcium release from intracellular stores may be followed by a homeostatic decrease in IP 3 -induced calcium release into the cytoplasm (Berridge et al, 2000), resulting in the altered calcium dynamics observed after 24 hours of paclitaxel treatment (Figure 6E).…”

Cockayne syndrome: Clinical features, model systems and pathways

“…Mitochondrial dysfunction also has important roles in neurodegeneration (Calì et al, 2012; Cheng et al, 2016b; Krols et al, 2016), that could be mediated through other neurotrophic factors such as brain-derived neurotrophic factor (Su et al, 2014). Recently, treatment with brain-derived neurotrophic factor was shown to overcome at least some of the neuritogenesis defects in CS cell lines (Wang et al, 2016).…”