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

ABSTRACT: 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. During Parkin-independent mitophagy, UBXD1 shows no mitochondrial translocation. Once translocated, UBXD1 recruits p97 to mitochondria via a bipartite binding motif consisting of its N-terminal VIM and PUB domains. Recruitment of p97 by UBXD1 only depends on the presence of UBXD1 on mitochondria without the need for further mitochondrial signals. Following translocation of UBXD1 to CCCP-depolarized mitochondria and p97 recruitment, formation of LC3-positive autolysosomes is strongly enhanced and autophagic degradation of mitochondria is significantly accelerated. Diminished levels of UBXD1 negatively impact mitophagic flux in Parkin-expressing cells after CCCP treatment. Thus, our data supports a model, whereby the p97 cofactor UBXD1 promotes Parkin-dependent mitophagy by specifically recognizing damaged mitochondria undergoing autophagic clearance.

SUBMITTER: Bento AC

PROVIDER: S-EPMC6098094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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. Thus, p97 likely plays a major role in mitochondrial maintenance. Support for this notion comes from mitochondrial dysfunction associated with amyotrophic lateral sclerosis and hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) caused by p97 mutation. Using SH-SY5Y cells stably expressing p97 or dominant-negative p97(QQ) treated with mitochondrial toxins rotenone, 6-OHDA, or A?-peptide as model for neuronal cells suffering from mitochondrial dysfunction, we found mitochondrial fragmentation under normal and stress conditions was significantly increased upon inactivation of p97. Furthermore, inactivation of p97 resulted in loss of mitochondrial membrane potential and increased production of reactive oxygen species (ROS). Under additional stress conditions, loss of mitochondrial membrane potential and increased ROS production was even more pronounced. Loss of mitochondrial fidelity upon inactivation of p97 was likely due to disturbed maintenance of mitochondrial proteostasis as the employed treatments neither induced mitophagy nor cell death. This was supported by the accumulation of oxidatively-damaged proteins on mitochondria in response to p97 inactivation. Dysfunction of p97 under normal and stress conditions in neuron-like cells severely impacts mitochondrial function, thus supporting for the first time a role for p97 as a major component of mitochondrial proteostasis.

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

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