PINK1 Loss-of-Function Mutations Affect Mitochondrial Complex I Activity via NdufA10 Ubiquinone Uncoupling

Morais, Vanessa A.; Haddad, Dominik; Craessaerts, Katleen; Bock, Pieter-Jan De; Swerts, Jef; Vilain, Sven; Aerts, Liesbeth; Overbergh, Lut; Grünewald, Anne; Seibler, Philip; Klein, Christine; Gevaert, Kris; Verstreken, Patrik; Strooper, Bart De

doi:10.1126/science.1249161

Cited by 300 publications

(275 citation statements)

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“…The lighter and sustained energy disturbance induced in the chronic model may have favored damage to the energy producing ability of energy sensitive DA cells and accumulated in them; whereas in the acute model, the severe energy disturbance was beyond the compensation ability of the tissues, therefore selective damage of DA cells was not induced. Therefore, future research into how the fragile cells were regulated to confront the energy stress may aid the elucidation of the underlying mechanisms of PD, which would build upon previous studies that have indicated PD-associated genes, parkin, phosphatase and tensin homolog-induced novel kinase-1 and DJ-1, are involved in energy crisis (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Rotenone-induced energy stress decompensated in ventral mesocerebrum is associated with Parkinsonism progression in rats

Bai

Tang³

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is characterized by the hallmark feature of loss of dopaminergic neurons in the substantia nigra. Energy metabolic disorder is associated with the pathogenesis of PD; however, the development of this disorder is yet to be elucidated. PD-like characteristics have been demonstrated in a rotenone rat model. In the present study, energy metabolism status was investigated in a rat model following intraperitoneal treatment with 1.0 mg/kg rotenone every 48 h. The behavior and tyrosine hydroxylase-positive levels in the substantia nigra of rats that were treated with rotenone for 24 weeks demonstrated that these rats developed more severe parkinsonism, as compared with that were treated for 16 weeks. Detection of ATP, lactic acid, NADH dehydrogenase 1 mRNA and lactate dehydrogenase B mRNA levels in the ventral mesocerebrum (VM) and skeletal muscle (SM) of the rats that had been treated with rotenone for 16 and 24 weeks demonstrated that the energy stress induced by rotenone progressed in both VM and SM. Notably, the energy stress detected in VM was more severe, and this energy stress was decompensated in the VM of rats that had been treated with rotenone for 24 weeks. The progression of energy stress and the incidence of energy decompensation in VM may be important for the improvement of PD pathology. IntroductionParkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra. PD is the most common neurodegenerative movement disorder, affecting >1% of the population that are aged >60 (1). Current treatments, such as pharmaceutical agents or deep brain stimulation predominantly target the symptoms and are unable to attenuate or reverse the progression of this disease (2). Understanding PD at a cellular and molecular level is important to determine novel targets and develop neuroprotective and disease-modifying therapeutic strategies. Although the causes and potential factors remain unknown, environmental factors may have a critical role, such as herbicides or pesticides, organic solvents, carbon monoxide and carbon disulfide (3,4). Notably, various studies have suggested that PD is associated with energy metabolism defects (5-7).Due to their structure, physiologic activities and high oxidative level of DA metabolism, DA cells in the substantia nigra are energy demanding and prone to energy stress (8). Furthermore, these cells have a relative low capacity for glycolysis compensation and lower glutathione levels (9,10), which ensures that they cannot respond appropriately to energy stress and are thus sensitive to energy disturbances.Rotenone is a common insecticide and mitochondria complex 1 inhibitor, which is used to induce chronic rotenone rat models with PD-associated features that manifest as DA cells are selectively damaged (11). However, how energy stress is induced and associated with the development of PD-associated in this model remains unknown.In the present study, rats were ...

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Section: Discussionmentioning

confidence: 99%

Rotenone-induced energy stress decompensated in ventral mesocerebrum is associated with Parkinsonism progression in rats

Bai

Tang³

et al. 2016

Experimental and Therapeutic Medicine

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“…The realization that these proteins are in a single pathway, with PINK1 acting upstream of Parkin to influence mitochondrial properties, was a critical step in uncovering the underlying pathological mechanisms of PD (5)(6)(7). This pathway can trigger the selective autophagy of damaged mitochondria, termed mitophagy (8,9), but additional cellular functions have also been indicated for PINK1 and Parkin (10)(11)(12)(13)(14)(15). Much, however, remains unclear about how the PINK1/Parkin pathway is regulated.…”

mentioning

confidence: 99%

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

124

116

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The PTEN-induced putative kinase 1 (PINK1)/Parkin pathway can tag damaged mitochondria and trigger their degradation by mitophagy. Before the onset of mitophagy, the pathway blocks mitochondrial motility by causing Miro degradation. PINK1 activates Parkin by phosphorylating both Parkin and ubiquitin. PINK1, however, has other mitochondrial substrates, including Miro (also called RhoT1 and -2), although the significance of those substrates is less clear. We show that mimicking PINK1 phosphorylation of Miro on S156 promoted the interaction of Parkin with Miro, stimulated Miro ubiquitination and degradation, recruited Parkin to the mitochondria, and via Parkin arrested axonal transport of mitochondria. Although Miro S156E promoted Parkin recruitment it was insufficient to trigger mitophagy in the absence of broader PINK1 action. In contrast, mimicking phosphorylation of Miro on T298/T299 inhibited PINK1-induced Miro ubiquitination, Parkin recruitment, and Parkin-dependent mitochondrial arrest. The effects of the T298E/T299E phosphomimetic were dominant over S156E substitution. We propose that the status of Miro phosphorylation influences the decision to undergo Parkin-dependent mitochondrial arrest, which, in the context of PINK1 action on other substrates, can restrict mitochondrial dynamics before mitophagy.is the second most common neurodegenerative disorder, and is closely linked to mitochondrial dysfunction (1, 2). Two hereditary forms of recessive PD are caused by mutations in PINK1 (PTEN-induced putative kinase 1), a Ser/Thr mitochondrial kinase, and Parkin, a cytosolic E3 ubiquitin ligase (3, 4). The realization that these proteins are in a single pathway, with PINK1 acting upstream of Parkin to influence mitochondrial properties, was a critical step in uncovering the underlying pathological mechanisms of PD (5-7). This pathway can trigger the selective autophagy of damaged mitochondria, termed mitophagy (8, 9), but additional cellular functions have also been indicated for PINK1 and Parkin (10-15). Much, however, remains unclear about how the PINK1/Parkin pathway is regulated.In current models of PINK1/Parkin mitophagy (reviewed in ref. 1), healthy mitochondria import a PINK1 precursor constitutively to the inner membrane, where it is cleaved (16-18). The cleaved form then returns to the cytoplasm and is degraded by the N-end rule pathway (19). Mitochondrial depolarization, or protein misfolding in the matrix of energized mitochondria (20), prevent the import and degradation of PINK1, resulting in the accumulation of PINK1 on the outer mitochondrial membrane (OMM) (9,21,22). Once on the OMM, PINK1 kinase activity recruits Parkin from the cytosol (8, 9). Although Parkin adopts a self-inhibited conformation in solution (23-25), it becomes fully activated in a PINK1-dependent manner on the mitochondria (9, 21). Parkin ubiquitinates numerous proteins of the OMM (26, 27), and thereby recruits autophagy-related proteins to the damaged mitochondrion for autophagosome assembly (28-30).How PINK1 recruits and activa...

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“…In pink1 mutant flies and cells, the enzymatic defects at the level of complex I result in a less negative mitochondrial membrane potential and less ATP production. Proteomic studies combined with in vivo rescue experiments in flies, mouse and patient derived cells subsequently provided evidence that pink1 deficiency results in defects to couple electron transport between complex I and ubiquinone (Morais et al, 2014). Both in flies and mammalian cells, the process of electron transfer at this level is facilitated by the phosphorylation of a specific complex I subunit NDUFA10, suggesting that therapeutic strategies that target this site may promote mitochondrial function (Morais et al, 2014;Pogson et al, 2014).…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

“…Proteomic studies combined with in vivo rescue experiments in flies, mouse and patient derived cells subsequently provided evidence that pink1 deficiency results in defects to couple electron transport between complex I and ubiquinone (Morais et al, 2014). Both in flies and mammalian cells, the process of electron transfer at this level is facilitated by the phosphorylation of a specific complex I subunit NDUFA10, suggesting that therapeutic strategies that target this site may promote mitochondrial function (Morais et al, 2014;Pogson et al, 2014). Further supporting this model, in flies, the mitochondrial defects in pink1 mutants are rescued by expression of a yeast protein, NDI1 that is able to bypass electron transport in complex I by feeding electrons straight into complex III (Pogson et al, 2014;Vilain et al, 2012).…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Flies with Parkinson's disease

Vanhauwaert

Verstreken

2015

Experimental Neurology

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PINK1 Loss-of-Function Mutations Affect Mitochondrial Complex I Activity via NdufA10 Ubiquinone Uncoupling

Cited by 300 publications

References 40 publications

Rotenone-induced energy stress decompensated in ventral mesocerebrum is associated with Parkinsonism progression in rats

Rotenone-induced energy stress decompensated in ventral mesocerebrum is associated with Parkinsonism progression in rats

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Flies with Parkinson's disease

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