VCP/p97 cofactor UBXN1/SAKS1 regulates mitophagy by modulating MFN2 removal from mitochondria.

Initiation of PINK1- and PRKN-dependent mitophagy is a highly regulated process involving the activity of the AAA-ATPase VCP/p97, a cofactor-guided multifunctional protein central to handling ubiquitinated client proteins. Removal of ubiquitinated substrates such as the mitofusin MFN2 from the outer mitochondrial membrane by VCP is critical for PRKN accumulation on mitochondria, which drives mitophagy. Here we characterize the role of the UBA and UBX-domain containing VCP cofactor UBXN1/SAKS1 during mitophagy.

Clearance of neurotoxic peptides and proteins by meningothelial cells.

Meningothelial cells (MECs) are the cellular component of the meninges that provide physical protection to the central nervous system (CNS). Their main function is the formation of a barrier enclosing the brain including the cerebrospinal fluid (CSF). Further, MECs are involved in maintaining CSF homeostasis by clearing CSF from bacteria and apoptotic cells.

UBXD1 is a mitochondrial recruitment factor for p97/VCP and promotes mitophagy.

Clearance of damaged mitochondria through mitophagy is critical for maintaining mitochondrial fidelity and the prevention of neurodegeneration. Here, we report on the UBX domain-containing, p97/VCP cofactor UBXD1/UBXN6/UBXDC2 and its role in mitophagy. Recognizing depolarized mitochondria via its C-terminal UBX domain, UBXD1 translocates to mitochondria in a Parkin-dependent manner.

Mitochondrial function in neuronal cells depends on p97/VCP/Cdc48-mediated quality control.

Maintaining mitochondrial function is essential for neuronal survival and offers protection against neurodegeneration. Ubiquitin-mediated, proteasome-dependent protein degradation in the form of outer mitochondrial membrane associated degradation (OMMAD) was shown to play roles in maintenance of mitochondria on the level of proteostasis, but also mitophagy and cell death. Recently, the AAA-ATPase p97/VCP/Cdc48 was recognized as part of OMMAD acting as retrotranslocase of ubiquitinated mitochondrial proteins for proteasomal degradation.

Quality control of oxidatively damaged mitochondrial proteins is mediated by p97 and the proteasome.

Protein quality control is essential for maintaining mitochondrial fidelity. Proteins damaged by reactive oxygen species necessitate quality control to prevent mitochondrial dysfunction connected to aging and neurodegeneration. Here we report a role for the AAA ATPase p97/VCP and the proteasome in the quality control of oxidized mitochondrial proteins under low oxidative stress as well as normal conditions.

Proteasome-mediated quality control of S-nitrosylated mitochondrial proteins.

Accumulating low level mitochondrial insults are thought to be key to aging processes and neurodegeneration. Among other stressors, protein damage due to nitrosative stress negatively impacts mitochondrial function and is linked to neurodegeneration. Using biotin switch technique, we show that mitochondrial proteins are S-nitrosylated not only in the presence but also in the absence of exogenous nitrosative stress.

Structural features within the nascent chain regulate alternative targeting of secretory proteins to mitochondria.

Protein targeting to specified cellular compartments is essential to maintain cell function and homeostasis. In eukaryotic cells, two major pathways rely on N-terminal signal peptides to target proteins to either the endoplasmic reticulum (ER) or mitochondria. In this study, we show that the ER signal peptides of the prion protein-like protein shadoo, the neuropeptide hormone somatostatin and the amyloid precursor protein have the property to mediate alternative targeting to mitochondria.

Inactivation of MARCH5 prevents mitochondrial fragmentation and interferes with cell death in a neuronal cell model.

Purpose: To study the impact of the mitochondrial ubiquitin ligase MARCH5 on mitochondrial morphology and induction of apoptosis using an in vitro model of neuronal precursor cells exposed to glaucoma-relevant stress conditions.

Methods: RGC5 cells transfected with expression constructs for MARCH5, MARCH5(H43W), Dpr1(K38A) or vector control were exposed to either elevated pressure of 30 mmHg, oxidative stress caused by mitochondrial electron transport chain (ETC) inhibition, or hypoxia-reoxygenation conditions. Mitochondrial morphology of RGC5 cells was analyzed following staining of the mitochondrial marker cytochrome c and photoactivatable GFP (PAGFP) diffusion assay.

Expression and role of the cell surface protease seprase/fibroblast activation protein-α (FAP-α) in astroglial tumors.

Seprase or fibroblast activation protein-α (FAP-α) is a cell-surface serine protease that was previously described nearly exclusively on reactive and tumor stromal fibroblasts and thought to be involved in tissue remodeling. We investigated the expression and significance of FAP-α in astrocytomas/glioblastomas. As shown by quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, FAP-α was elevated in whole glioblastoma tissues and in particular in most glioma cells in situ and in vitro.