Publication date: Jul 03, 2025
Mitochondrial integrity is a crucial determinant of overall cellular health. Mitochondrial dysfunction and impediments in regulating organellar homeostasis contribute majorly to the pathophysiological manifestation of several neurological disorders. Mutations in human DJ-1 (PARK7) have been implicated in the deregulation of mitochondrial homeostasis, a critical cellular etiology observed in Parkinson’s disease progression. DJ-1 is a multifunctional protein belonging to the DJ-1/ThiJ/PfpI superfamily, conserved across the phylogeny. Although the pathophysiological significance of DJ-1 has been well-established, the underlying molecular mechanism(s) by which DJ-1 paralogs modulate mitochondrial maintenance and other cellular processes remains elusive. Using Saccharomyces cerevisiae as the model organism, we unravel the intricate mechanism by which yeast DJ-1 paralogs (collectively called Hsp31 paralogs) modulate mitochondrial homeostasis. Our study establishes a genetic synthetic interaction between Ubp2, a cysteine-dependent deubiquitinase, and DJ-1 paralogs. In the absence of DJ-1 paralogs, mitochondria adapt to a highly tubular network due to enhanced expression of Fzo1. Intriguingly, the loss of Ubp2 restores the mitochondrial integrity in the DJ-1 deletion background by modulating the ubiquitination status of Fzo1. Besides, the loss of Ubp2 in the absence of DJ-1 restores mitochondrial respiration and functionality by regulating the mitophagic flux. Further, Ubp2 deletion makes cells resistant to oxidative stress without DJ-1 paralogs. For the first time, our study deciphers functional crosstalk between Ubp2 and DJ-1 in regulating mitochondrial homeostasis and cellular health.
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Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | Mitochondrial dysfunction |
| disease | MESH | neurological disorders |
| disease | MESH | etiology |
| disease | MESH | disease progression |
| drug | DRUGBANK | L-Cysteine |
| disease | MESH | oxidative stress |
| disease | MESH | neurodegenerative disorders |
| pathway | REACTOME | Metabolism |
| pathway | REACTOME | Reproduction |
| drug | DRUGBANK | Dihydrostreptomycin |
| pathway | REACTOME | SUMOylation |
| pathway | REACTOME | Deubiquitination |
| drug | DRUGBANK | Isoxaflutole |
| disease | MESH | defects |
| drug | DRUGBANK | Glycerin |
| drug | DRUGBANK | Dextrose unspecified form |
| drug | DRUGBANK | Coenzyme M |
| drug | DRUGBANK | Activated charcoal |
| drug | DRUGBANK | Pentaerythritol tetranitrate |
| drug | DRUGBANK | L-Leucine |