Valosin-Containing Protein, a Calcium-Associated ATPase Protein, in Endoplasmic Reticulum and Mitochondrial Function and Its Implications for Diseases

Abstract

Endoplasmic reticulum (ER) and mitochondrion are the key organelles in mammal cells and play crucial roles in a variety of biological functions in both physiological and pathological conditions. Valosin-containing protein (VCP), a newly identified calcium-associated ATPase protein, has been found to be involved in both ER and mitochondrial function. Impairment of VCP, caused by structural mutations or alterations of expressions, contributes to the development of various diseases, through an integrating effect on ER, mitochondria and the ubiquitin–proteasome system, by interfering with protein degradation, subcellular translocation and calcium homeostasis. Thus, understanding the role and the molecular mechanisms of VCP in these organelles brings new insights to the pathogenesis of the associated diseases, and leads to the discovery of new therapeutic strategies. In this review, we summarized the progress of studies on VCP, in terms of its regulation of ER and mitochondrial function and its implications for the associated diseases, focusing on the cancers, heart disease, and neurodegenerative disorders.

Amyotrophic Lateral Sclerosis (ALS): Stressed by Dysfunctional Mitochondria-Endoplasmic Reticulum Contacts (MERCs)

“…Given normal MERCs are an important point of origin for autophagosomal membranes [ 164 ], mutant VCP also leads to reduced autophagic clearance of TDP-43 and FUS aggregates [ 165 , 166 ], potentially through Beclin-1-dependent autophagy initiation [ 167 ] or through the inhibition of the PINK/Parkin pathway [ 168 ]. Similar to the findings with VAPB, VCP mutations are associated with disrupted metabolic signaling between the ER and mitochondria [ 169 ].…”

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

“…VCP/p97 is a multifunctional protein with a considerable effect on protein metabolism and intracellular homeostasis because it functions as a segregase to extract target proteins from the cellular organelle membrane, DNA complexes or protein complexes and promotes their degradation, refolding, recycling and relocation [ 8 , 9 ]. VCP/p97 interacts with multiple cofactors that are also directly correlated ( Figure 2 ) and recruits proteins to different subcellular locations to participate in diverse cellular processes, such as endoplasmic reticulum-associated protein degradation (ERAD), chromatin-associated degradation, endosomal trafficking, aggregate trafficking, autophagy, induction of proteasome gene expression, lipid droplet biogenesis, ribosomal-associated degradation, mitochondria-associated degradation, apoptosis, cell cycle regulation and Golgi assembly ( Figure 3 ) [ 10 ]. Multiple VCP/p97 cofactors share common binding motifs and conserved binding modules, such as the UBX (ubiquitin regulatory X) domain, UBXL (UBX-like) domain, VBM (VCP/p97-binding motif) and VIM (VCP/p97-interacting motif).…”

Structural and Functional Remodeling of Mitochondria in Cardiac Diseases

“…Serval studies disputed that Ca 2+ uptake in cardiac mitochondria might be limited under the physiological condition due to the lower expression levels of the uniporter compared to other tissues [ 48 , 49 ]. It showed that mitochondria regulate Ca 2+ homeostasis by communicating with the SR via mitochondria-associated ER membranes (MAMs) [ 50 , 51 , 52 ]. The function of ER-mitochondria interaction is regulated by several factors located on the MAMs, such as inositol 1,4,5-trisphosphate (IP3) receptor (IP3Rs), voltage-dependent anion-selective channel 1 (VDAC1), and glucose-regulated protein 75 (Grp75), plays a critical role in the ER-mitochondrial Ca 2+ transfer [ 53 ].…”