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.

Keywords: calcium homeostasis; disease; endoplasmic reticulum; mitochondria; valosin-containing protein.

Figure 1

The scheme of the mammalian isoform of VCP domains and their function. VCP is constituted by one binding domain N-domain, two ATPase domains (D1 domain and D2 domain) and a C-terminus. N-domains are responsible for substrate recognition and binding. The D2 domain contributes to the major ATPase activity of VCP, while the D1 domain is responsible for the assembly of VCP homohexamer. The N-domain and D1 domain are connected by an N-D1 linker, and the D1 and D2 domains are connected by D1–D2 linker.

Figure 2

Summary of the integrating regulation of VCP on ER- and mitochondrial-associated degradation and calcium homeostasis. VCP plays an essential role in maintaining cellular function and calcium homeostasis in physiological conditions through multiple mechanisms. By interacting with other proteins, VCP participates in the delivery of misfolded proteins from the ER (a) and promotes the ubiquitin-dependent degradation processes through the ubiquitin–proteasome system (UPS) during ERAD (b). VCP is also involved in extracting the misfolded proteins from mitochondria during the process of mitochondria-associated degradation, and participates in mitophagy-related degradation (c). VCP participates in the regulation of calcium homeostasis through mitochondria-associated ER membranes (MAMs), which stimulates electron activity and ATP production (d). Reciprocally, VCP prevents excessive calcium entry in mitochondria by regulating the mitochondrial calcium intake through the degradation of mitochondrial calcium uptake (MICU) proteins (e), which subsequently inhibits mPTP opening, preventing cell death. Impairment of VCP activity induces ER and mitochondrial dysfunctions, which subsequently induce cellular damage, resulting in the pathogenesis of the diseases.

Figure 3

Summary of the common features related to VCP in different diseases. Despite the fact that the cofactors and the regulatory signaling pathways underlying the pathogenesis of these disorders may vary, VCP could promote stress-induced misfolded protein degradation and maintain calcium homeostasis, which subsequently helps resist ER/mitochondrial stress-induced cell damage and death. As the increase of VCP in cancer cells would protect cells against death, the deficiency of VCP in neurodegenerative disorders and heart diseases would induce cell damage and death, due to the loss of these functions. (The red arrows represent the promotive effects and green arrows stand for the inhibitory/suppressive effects).