ER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43

Abstract

Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER–mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER–mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER–mitochondria interactions and that this is associated with disruption to the VAPB–PTPIP51 interaction and cellular Ca2+ homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB–PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.

A Fungal Sarcolemmal Membrane-Associated Protein (SLMAP) Homolog Plays a Fundamental Role in Development and Localizes to the Nuclear Envelope, Endoplasmic Reticulum, and Mitochondria

“…ERMES, a homolog of which has not yet been identified in higher eukaryotes, was suggested to be involved in phospholipid exchange, calcium signaling, and mitochondrial physiology (70)(71)(72). Recently, ER-mitochondrion contact sites have been shown to play a role in neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis (73,74).…”

Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection

“…Abnormal mitochondrial ultrastructure is also observed in SOD1 mutant mice, which may cause defects in mitochondrial trafficking (Magrané et al, 2009) Additionally, aberrant interaction of mutant SOD1 with OMM proteins such as VDAC1 can cause mitochondrial damage, and mutant SOD1 aggregates accumulate inside mitochondria causing oxidative stress (Palomo and Manfredi, 2015). Mutant TDP-43 conversely, forms aggregates which reduce contacts sites between mitochondria and the endoplasmic reticulum, possibly through and interaction with Mfn-2 (Stoica et al, 2014;Wang et al, 2013). Perturbations to these contacts sites lead to deregulation of mitochondrial Ca 2+ homeostasis.…”

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

“…[86][87][88][89][90] Murine models have illustrated loss of function mutations altering the unfolded protein response pathway, reducing functional myotubule formation 91 and this model has been illustrated in human samples elsewhere. 86,92 Additional murine studies have demonstrated progressive hyperactivity and motor impairment due to corticospinal and spinal motor neuron destruction in VABP transgenic mice.…”