ArticlePharmacological reports : PR2026
Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
Article in Pharmacological reports : PR, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundMitochondrial DNA (mtDNA) diseases are heterogeneous and lack effective treatments. Their severity correlates with mutant mtDNA load. Mitophagy degrades dysfunctional mitochondria, contributing to a healthy mitochondrial pool. USP30, a mitochondrial deubiquitinase, limits mitophagy by removing the ubiquitin tagging mitochondria for degradation. We investigated whether inhibiting USP30 could enhance mitophagy and reduce mutant mtDNA load in a heteroplasmic mitochondrial disease.
methodsCybrids cells harboring mutant m.8993T > G mtDNA - common cause of NARP syndrome and maternally inherited Leigh syndrome (MILS) - were treated with USP30 inhibitor MF-094 under glycolytic and oxidative phosphorylation conditions. On-target activity of MF-094 was assessed by mitochondrial ubiquitination (western-blot) and mitolysosome formation (microscopy). The mutation’s effects were investigated on cell proliferation and metabolism (respirometry and ATP levels). The impact of MF-094 on mutant mtDNA load and mtDNA copy number was quantified by PCR.
resultsComparing with control cells (0% mutant mtDNA), cells with mutant mtDNA exhibited reduced proliferation and ATP levels under oxidative phosphorylation conditions; and reduced oxygen consumption, increased extracellular acidification, and sustained resazurin metabolism after mitochondrial inhibition under glycolytic conditions. MF-094 induced mitophagy via increased mitolysosome formation. Mechanistically, MF-094 showed on-target effects, increasing mitochondrial ubiquitination. However, chronic treatment (3–6 weeks) evoked only a small (5%) non-significant reduction in mutant mtDNA load.
conclusionsDespite inducing mitophagy, the USP30 inhibitor MF-094 showed little potential to manage m.8993T > G related diseases, as it did not significantly reduce the load of this NARP/MILS causing mtDNA mutation. These results highlight the complexity of mutant mtDNA management and the need for innovative strategies for these disorders.
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