Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand

McWilliams, Thomas G.; Prescott, Alan R.; Montava-Garriga, Lambert; Ball, Graeme; Singh, François; Barini, Erica; Muqit, Miratul M. K.; Brooks, Simon Philip; Ganley, Ian G.

doi:10.1016/j.cmet.2017.12.008

Cited by 472 publications

(497 citation statements)

References 51 publications

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“…We wondered whether, by analogy with the role of USP30 in Parkin-overexpressing cells, this increase in mitophagy was dependent on PINK1. Depleting PINK1 did not affect basal levels of mitophagy, in agreement with two recent reports in mitophagy reporter flies and mice [19,20]. However, PINK1 depletion did suppress the enhancement of mitophagy seen upon USP30 knockdown ( Fig 1D).…”

Section: Enhancement Of Basal Mitophagy By Usp30 Depletion Is Dependesupporting

confidence: 92%

Dual role of USP 30 in controlling basal pexophagy and mitophagy

et al. 2018

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USP30 is an integral protein of the outer mitochondrial membrane that counteracts PINK1 and Parkin‐dependent mitophagy following acute mitochondrial depolarisation. Here, we use two distinct mitophagy reporter systems to reveal tonic suppression by USP30, of a PINK1‐dependent component of basal mitophagy in cells lacking detectable Parkin. We propose that USP30 acts upstream of PINK1 through modulation of PINK1‐substrate availability and thereby determines the potential for mitophagy initiation. We further show that a fraction of endogenous USP30 is independently targeted to peroxisomes where it regulates basal pexophagy in a PINK1‐ and Parkin‐independent manner. Thus, we reveal a critical role of USP30 in the clearance of the two major sources of ROS in mammalian cells and in the regulation of both a PINK1‐dependent and a PINK1‐independent selective autophagy pathway.

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Section: Enhancement Of Basal Mitophagy By Usp30 Depletion Is Dependesupporting

confidence: 92%

Dual role of USP 30 in controlling basal pexophagy and mitophagy

et al. 2018

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“…Accordingly, a number of outer mitochondrial membrane (OMM) proteins, including mitofusins, VDACs and subunits of the translocase of the OMM (TOM) interact with or are ubiquitinated by Parkin during the process of mitochondrial clearance in response to mitochondrial depolarization 23 , suggesting that no specific substrate is required for ubiquitin signalling of mitophagy. However, the finding that loss of PINK1 did not influence basal mitophagy despite disrupting depolarization-induced Parkin activation 24 , suggests that Parkin could participate in maintain mitochondrial integrity by different pathways. Parkin was shown to constitutively associate with the ER and the mitochondrial membranes under basal conditions 25–31 implying a potential role for this protein in mitophagy-independent functions, such as the modulation of the proteasome activity, of the mitochondrial–ER interactions and calcium crosstalk and the degradation or targeting of specific mitochondrial and/or mitochondria-related proteins.…”

Section: Introductionmentioning

confidence: 95%

Parkin-dependent regulation of the MCU complex component MICU1

Matteucci

Patrón

Reane

et al. 2018

Sci Rep

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The mitochondrial Ca2+ uniporter machinery is a multiprotein complex composed by the Ca2+ selective pore-forming subunit, the mitochondrial uniporter (MCU), and accessory proteins, including MICU1, MICU2 and EMRE. Their concerted action is required to fine-tune the uptake of Ca2+ into the mitochondrial matrix which both sustains cell bioenergetics and regulates the apoptotic response. To adequately fulfil such requirements and avoid impairment in mitochondrial Ca2+ handling, the intracellular turnover of all the MCU components must be tightly regulated. Here we show that the MCU complex regulator MICU1, but not MCU and MICU2, is rapidly and selectively degraded by the Ubiquitin Proteasome System (UPS). Moreover, we show that the multifunctional E3 ubiquitin ligase Parkin (PARK2), whose mutations cause autosomal recessive early-onset Parkinson’s disease (PD), is a potential candidate involved in this process since its upregulation strongly decreases the basal level of MICU1. Parkin was found to interact with MICU1 and, interestingly, Parkin Ubl-domain, but not its E3-ubquitin ligase activity, is required for the degradation of MICU1, suggesting that in addition to the well documented role in the control of Parkin basal auto-inhibition, the Ubl-domain might exert important regulatory functions by acting as scaffold for the proteasome-mediated degradation of selected substrates under basal conditions, i.e. to guarantee their turnover. We have found that also MICU2 stability was affected upon Parkin overexpression, probably as a consequence of increased MICU1 degradation. Our findings support a model in which the PD-related E3 ubiquitin ligase Parkin directly participates in the selective regulation of the MCU complex regulator MICU1 and, indirectly, also of the MICU2 gatekeeper, thus indicating that Parkin loss of function could contribute to the impairment of the ability of mitochondria to handle Ca2+ and consequently to the pathogenesis of PD.

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“…Of the various mitochondrial ubiquitin ligases (Covill‐Cooke et al , ), we studied March5 and MUL1, because they are known to be expressed in the nervous system, but it is possible that other ubiquitin ligases are involved. In support of this interpretation, it was recently demonstrated that in transgenic mice expressing a mitophagy reporter, the ablation of PINK1 did not affect the rate of basal mitophagy in neurons (McWilliams et al , ), further indicating that the loss of PINK1‐Parkin in the nervous system can be complemented by other MQC mechanisms.…”

Section: Discussionmentioning

confidence: 86%

Parkin is a disease modifier in the mutant SOD 1 mouse model of ALS

et al. 2018

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Mutant Cu/Zn superoxide dismutase (SOD1) causes mitochondrial alterations that contribute to motor neuron demise in amyotrophic lateral sclerosis (ALS). When mitochondria are damaged, cells activate mitochondria quality control (MQC) mechanisms leading to mitophagy. Here, we show that in the spinal cord of G93A mutant SOD1 transgenic mice (SOD1‐G93A mice), the autophagy receptor p62 is recruited to mitochondria and mitophagy is activated. Furthermore, the mitochondrial ubiquitin ligase Parkin and mitochondrial dynamics proteins, such as Miro1, and Mfn2, which are ubiquitinated by Parkin, and the mitochondrial biogenesis regulator PGC1α are depleted. Unexpectedly, Parkin genetic ablation delays disease progression and prolongs survival in SOD1‐G93A mice, as it slows down motor neuron loss and muscle denervation and attenuates the depletion of mitochondrial dynamics proteins and PGC1α. Our results indicate that Parkin is a disease modifier in ALS, because chronic Parkin‐mediated MQC activation depletes mitochondrial dynamics‐related proteins, inhibits mitochondrial biogenesis, and worsens mitochondrial dysfunction.

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Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand

Cited by 472 publications

References 51 publications

Dual role of USP 30 in controlling basal pexophagy and mitophagy

Dual role of USP 30 in controlling basal pexophagy and mitophagy

Parkin-dependent regulation of the MCU complex component MICU1

Parkin is a disease modifier in the mutant SOD 1 mouse model of ALS

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