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

Sun, Xiaonan; Qiu, Hongyu

doi:10.3390/ijms21113842

Cited by 20 publications

(26 citation statements)

References 81 publications

(108 reference statements)

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“…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 ].…”

Section: Als-associated Stress Signaling Converges On Membrane Contact Sitessupporting

confidence: 72%

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

Chen

Bassot

Giuliani

et al. 2021

Cells

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is currently no cure. Progress in the characterization of other neurodegenerative mechanisms has shifted the spotlight onto an intracellular structure called mitochondria-endoplasmic reticulum (ER) contacts (MERCs) whose ER portion can be biochemically isolated as mitochondria-associated membranes (MAMs). Within the central nervous system (CNS), these structures control the metabolic output of mitochondria and keep sources of oxidative stress in check via autophagy. The most relevant MERC controllers in the ALS pathogenesis are vesicle-associated membrane protein-associated protein B (VAPB), a mitochondria-ER tether, and the ubiquitin-specific chaperone valosin containing protein (VCP). These two systems cooperate to maintain mitochondrial energy output and prevent oxidative stress. In ALS, mutant VAPB and VCP take a central position in the pathology through MERC dysfunction that ultimately alters or compromises mitochondrial bioenergetics. Intriguingly, both proteins are targets themselves of other ALS mutant proteins, including C9orf72, FUS, or TDP-43. Thus, a new picture emerges, where different triggers cause MERC dysfunction in ALS, subsequently leading to well-known pathological changes including endoplasmic reticulum (ER) stress, inflammation, and motor neuron death.

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Section: Als-associated Stress Signaling Converges On Membrane Contact Sitessupporting

confidence: 72%

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

Chen

Bassot

Giuliani

et al. 2021

Cells

View full text Add to dashboard Buy / Rent full text

show abstract

“…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 ].…”

Section: Mitochondrial Remodeling In Cardiac Diseasesmentioning

confidence: 99%

Structural and Functional Remodeling of Mitochondria in Cardiac Diseases

Sun

Alford

Qiu

2021

IJMS

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Mitochondria undergo structural and functional remodeling to meet the cell demand in response to the intracellular and extracellular stimulations, playing an essential role in maintaining normal cellular function. Merging evidence demonstrated that dysregulation of mitochondrial remodeling is a fundamental driving force of complex human diseases, highlighting its crucial pathophysiological roles and therapeutic potential. In this review, we outlined the progress of the molecular basis of mitochondrial structural and functional remodeling and their regulatory network. In particular, we summarized the latest evidence of the fundamental association of impaired mitochondrial remodeling in developing diverse cardiac diseases and the underlying mechanisms. We also explored the therapeutic potential related to mitochondrial remodeling and future research direction. This updated information would improve our knowledge of mitochondrial biology and cardiac diseases’ pathogenesis, which would inspire new potential strategies for treating these diseases by targeting mitochondria remodeling.

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“…For example, VCP/p97 K524A transgenic mice exhibit cardiomyopathy with the accumulation of ubiquitinated proteins [ 10 ]. In addition to protein homeostasis, VCP/p97 also plays a vital role in the maintenance of mitochondrial function and the promotion of cardiomyocyte survival [ 40 ]. In the following sections, we have summarized certain basic findings concerning VCP/p97 in cardiovascular diseases.…”

Section: Vcp/p97 and Cardiovascular Diseasesmentioning

confidence: 99%

Emerging role of VCP/p97 in cardiovascular diseases: novel insights and therapeutic opportunities

Shu

Peng

Hang

et al. 2021

Biochemical Society Transactions

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Valosin-containing protein (VCP/p97) is a member of the conserved type II AAA+ (ATPases associated with diverse cellular activities) family of proteins with multiple biological functions, especially in protein homeostasis. Mutations in VCP/p97 are reportedly related to unique autosomal dominant diseases, which may worsen cardiac function. Although the structure of VCP/p97 has been clearly characterized, with reports of high abundance in the heart, research focusing on the molecular mechanisms underpinning the roles of VCP/p97 in the cardiovascular system has been recently undertaken over the past decades. Recent studies have shown that VCP/p97 deficiency affects myocardial fibers and induces heart failure, while overexpression of VCP/p97 eliminates ischemia/reperfusion injury and relieves pathological cardiac hypertrophy caused by cardiac pressure overload, which is related to changes in the mitochondria and calcium overload. However, certain studies have drawn opposing conclusions, including the mitigation of ischemia/reperfusion injury via inhibition of VCP/p97 ATPase activity. Nevertheless, these emerging studies shed light on the role of VCP/p97 and its therapeutic potential in cardiovascular diseases. In other words, VCP/p97 may be involved in the development of cardiovascular disease, and is anticipated to be a new therapeutic target. This review summarizes current findings regarding VCP/p97 in the cardiovascular system for the first time, and discusses the role of VCP/p97 in cardiovascular disease.

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

Cited by 20 publications

References 81 publications

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

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

Structural and Functional Remodeling of Mitochondria in Cardiac Diseases

Emerging role of VCP/p97 in cardiovascular diseases: novel insights and therapeutic opportunities

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