Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial dysfunction is a prominent feature of neurodegenerative diseases and aging. A recent study showed that phosphorylation of dynamin-related protein 1 (Drp1) is increased in Alzheimer's disease (AD) brains compared to control brains, indicating that mitochondrial fission is increased in AD brains. Here, we showed that Drp1 phosphorylation and mitochondrial fission were also increased in rat cortical neurons treated with okadaic acid (OA), which inhibits protein phosphatase-2A (PP2A) and induces AD-like tau phosphorylation and neuronal death. Concurrent with this abnormal increase in mitochondrial fission, mitochondrial reactive oxygen species (ROS) were also increased, suggesting mitochondrial damage and detrimental effects on cell survival. Parkin, which is necessary for mitophagy of abnormal mitochondria and has been shown to be decreased in AD brains, and K48-linked polyubiquitin were also decreased in OA-treated neurons, suggesting that the mitophagic process required to degrade detrimental ROS-generating mitochondria is disabled. Collectively, our results demonstrate that abnormal mitochondrial fission, ROS generation, and inefficient mitophagy all occur in PP2A-inhibited neurons, as in AD brains, and suggest that this model could be used in developing inhibitors of mitochondrial fission or ROS generation.
 ...
PMID:Increased phosphorylation of dynamin-related protein 1 and mitochondrial fission in okadaic acid-treated neurons. 2245 49

Ubiquitin- and proteasome-dependent outer mitochondrial membrane (OMM)-associated degradation (OMMAD) is critical for mitochondrial and cellular homeostasis. However, the scope and molecular mechanisms of the OMMAD pathways are still not well understood. We report that the OMM-associated E3 ubiquitin ligase MARCH5 controls dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and cell sensitivity to stress-induced apoptosis. MARCH5 knockout selectively inhibited ubiquitination and proteasomal degradation of MiD49, a mitochondrial receptor of Drp1, and consequently led to mitochondrial fragmentation. Mitochondrial fragmentation in MARCH5(-/-) cells was not associated with inhibition of mitochondrial fusion or bioenergetic defects, supporting the possibility that MARCH5 is a negative regulator of mitochondrial fission. Both MARCH5 re-expression and MiD49 knockout in MARCH5(-/-) cells reversed mitochondrial fragmentation and reduced sensitivity to stress-induced apoptosis. These findings and data showing MARCH5-dependent degradation of MiD49 upon stress support the possibility that MARCH5 regulation of MiD49 is a novel mechanism controlling mitochondrial fission and, consequently, the cellular response to stress.
 ...
PMID:Mitochondrial E3 ubiquitin ligase MARCH5 controls mitochondrial fission and cell sensitivity to stress-induced apoptosis through regulation of MiD49 protein. 2656 96