Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy

Cellular quality control systems have gained much attention in recent decades. Among these, autophagy is a natural self-preservation mechanism that continuously eliminates toxic cellular components and acts as an anti-ageing process. It is vital for cell survival and to preserve homeostasis. Several cell-type-dependent canonical or non-canonical autophagy pathways have been reported showing varying degrees of selectivity with regard to the substrates targeted. Here, we provide an updated review of the autophagy machinery and discuss the role of various forms of autophagy in neurodegenerative diseases, with a particular focus on Parkinson’s disease. We describe recent findings that have led to the proposal of therapeutic strategies targeting autophagy to alter the course of Parkinson’s disease progression.

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“…Treatment with MF-094 has shown potent protein ubiquitination and accelerated mitophagy in vitro [ 132 , 200 , 269 ].…”

Section: Figurementioning

confidence: 99%

Autophagy-Lysosomal Pathway as Potential Therapeutic Target in Parkinson’s Disease

Bonam

Tranchant

Muller

2021

Cells

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“…This shift into the spotlight has highlighted an unmet need for tools to manipulate pexophagy in a controlled manner. Here, we started out by surveying a number of candidate compounds and discovered that the neddylation inhibitor MLN4924 and the USP30 inhibitor compound 39 (CMPD-39) are both potent inducers of pexophagy ( 20 , 21 ). In parallel to mitophagy, we show that the MLN4924 effect reflects activation of HIF1α and up-regulation of NIX.…”

Section: Introductionmentioning

confidence: 99%

Segregation of pathways leading to pexophagy

2023

Self Cite

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Peroxisomes are organelles with key roles in metabolism including long-chain fatty acid production. Their metabolic functions overlap and interconnect with those of mitochondria, with which they share an overlapping but distinct proteome. Both organelles are degraded by selective autophagy processes termed pexophagy and mitophagy. Although mitophagy has received intense attention, the pathways linked to pexophagy and associated tools are less well developed. We have identified the neddylation inhibitor MLN4924 as a potent activator of pexophagy and show that this is mediated by the HIF1α-dependent up-regulation of BNIP3L/NIX, a known adaptor for mitophagy. We show that this pathway is distinct from pexophagy induced by the USP30 deubiquitylase inhibitor CMPD-39, for which we identify the adaptor NBR1 as a central player. Our work suggests a level of complexity to the regulation of peroxisome turnover that includes the capacity to coordinate with mitophagy, via NIX, which acts as a rheostat for both processes.

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“…Interestingly, our data indicate that USP30 inhibition facilitates mitophagy in parkin-deficient neurons at both basal growth conditions and upon CCCP-stress. In line with this, USP30 inhibition increases mitophagy in induced neurons derived from parkin loss-of-function carriers [46]. Moreover, defective mitophagy in SH-SY5Y cells transfected with PD-linked parkin mutants can be rescued with siRNA mediated knockdown of USP30 [13, 47].…”

Section: Discussionmentioning

confidence: 94%

USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient and CCCP-stressed human iPSC-derived neurons

Okarmus

Agergaard

Stummann

et al. 2022

Preprint

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Ubiquitination of mitochondrial proteins plays an important role in the cellular regulation of mitophagy. The E3 ubiquitin ligase parkin (encoded by PARK2) and the ubiquitin-specific protease 30 (USP30) have both been reported to regulate ubiquitination of outer mitochondrial proteins and thereby mitophagy. Loss of E3 ligase activity is thought to be pathogenic in both sporadic and inherited Parkinson's disease (PD), with loss-of-function mutations in PARK2 being the most frequent cause of autosomal recessive PD. The aim of the present study was to evaluate whether mitophagy induced by USP30 inhibition provides a functional rescue in isogenic human induced pluripotent stem cell-derived dopaminergic neurons with and without PARK2 knockout (KO). Our data show that healthy neurons responded to CCCP-induced mitochondrial damage by clearing the impaired mitochondria and that this process was accelerated by USP30 inhibition. Parkin-deficient neurons showed an impaired mitophagic response to CCCP challenge, although mitochondrial ubiquitination was enhanced. USP30 inhibition promoted mitophagy in PARK2 KO neurons, independently of whether left in basal conditions or treated with CCCP. In PARK2 KO, as in control neurons, USP30 inhibition balanced oxidative stress levels by reducing excessive production of reactive oxygen species. Interestingly, non-dopaminergic neurons, were the main driver of the beneficial effects of USP30 inhibition. Our findings demonstrate that USP30 inhibition is a promising approach to boost mitophagy and improve cellular health, also in parkin-deficient cells, and support the potential relevance of USP30 inhibitors as a novel therapeutic approach in diseases with a need to combat neuronal stress mediated by impaired mitochondria.

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Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy

Cited by 36 publications

References 41 publications

Autophagy-Lysosomal Pathway as Potential Therapeutic Target in Parkinson’s Disease

Autophagy-Lysosomal Pathway as Potential Therapeutic Target in Parkinson’s Disease

Segregation of pathways leading to pexophagy

USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient and CCCP-stressed human iPSC-derived neurons

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