The Parkinson's disease–linked proteins Fbxo7 and Parkin interact to mediate mitophagy

Burchell, Victoria; Nelson, David E.; Sánchez-Martínez, Álvaro; Delgado-Camprubi, Marta; Ivatt, Rachael M.; Pogson, Joe H.; Randle, Suzanne J.; Wray, Selina; Lewis, Patrick A.; Houlden, Henry; Abramov, Andrey Y.; Hardy, John; Wood, Nicholas W.; Whitworth, Alexander J.; Laman, Heike; Plun‐Favreau, Hélène

doi:10.1038/nn.3489

Cited by 295 publications

(341 citation statements)

References 46 publications

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“…Alternatively, cells were fixed for immunocytochemistry in a 4% PFA PBS solution for 10 min at room temperature (16). Antibodies used were: anti-Pink1 (Novus Biologicals BC100 -494 1:1000), mouse anti-FLAG (Sigma F3165, 1:2,000), rabbit anti-FLAG (Sigma F7425, 1:5,000), anti-complex V␤ subunit (Abcam ab14730, 1:500), anti-Mfn1 (Abcam ab57602, 1:1,000 for WB), antiComplex V␣ (1:5,000, Abcam ab14730), HtrA2 (Cell Signaling, 1:4000) anti-LC3 (Novus NB100 -2220).…”

Section: Methodsmentioning

confidence: 99%

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Intracellular pH Modulates Autophagy and Mitophagy

Berezhnov

Soutar

Fedotova

et al. 2016

Journal of Biological Chemistry

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The specific autophagic elimination of mitochondria (mitophagy) plays the role of quality control for this organelle. Deregulation of mitophagy leads to an increased number of damaged mitochondria and triggers cell death. The deterioration of mitophagy has been hypothesized to underlie the pathogenesis of several neurodegenerative diseases, most notably Parkinson disease. Although some of the biochemical and molecular mechanisms of mitochondrial quality control are described in detail, physiological or pathological triggers of mitophagy are still not fully characterized. Here we show that the induction of mitophagy by the mitochondrial uncoupler FCCP is independent of the effect of mitochondrial membrane potential but dependent on acidification of the cytosol by FCCP. The ionophore nigericin also reduces cytosolic pH and induces PINK1/PARKIN-dependent and -independent mitophagy. The increase of intracellular pH with monensin suppresses the effects of FCCP and nigericin on mitochondrial degradation. Thus, a change in intracellular pH is a regulator of mitochondrial quality control.Continuous ATP production is essential for cell survival. Mitochondria are the major ATP producers in the cell; these are distributed throughout different tissues in varying amounts depending on energy demand. The number of mitochondria within cells is regulated by the balance between mitochondrial biogenesis (1) and the removal of damaged mitochondria. Furthermore, mitochondria also regulate cell death, which is triggered by release of intramitochondrial proteins (2). Considering this, the removal of dysfunctional mitochondria is an important process for ensuring cell survival.Damaged mitochondria, as well as other impaired organelles and proteins in cells are degraded by specific autophagy. Mitochondrial autophagy (mitophagy) 2 plays a role in the quality control of this organelle, whereas dysfunction in mitophagy can lead to an increase in the number of damaged mitochondria that can trigger the activation of cell death pathways (3, 4). Over the last several years, a number of studies have provided substantial evidence showing the PINK1-Parkin pathway (familial forms of Parkinson disease caused by mutations in the genes encoding the PTEN (phosphatase and tensin homolog)-induced putative kinase-1 (PINK1) and Parkin E3 ubiquitin ligase) promotes mitophagy. PINK1 accumulates at the outer mitochondrial membrane of depolarized mitochondria, which recruits cytoplasmic Parkin to the damaged organelle. This results in the ubiquitination of mitofusins (Mfns) by Parkin, the engulfment of the dysfunctional mitochondria by autophagosomes, and subsequent mitophagy (5-8). In recent years, abnormal autophagy and mitophagy has been shown for toxininjured dopaminergic neurons as well as in all the major genetic models of Parkinson disease (PD), including ␣-synuclein, leucine-rich repeat kinase 2 (LRRK2), parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 (9, 10). Historically, mitophagy research focuses on the biochemical and molecular mechanisms of PD; ...

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Section: Methodsmentioning

confidence: 99%

“…Here we show that FCCP changes intracellular pH, which induces mitophagy. Importantly, other physiological processes that induce mitophagy, such as hypoxia and starvation, also induce mild acidification of the cytosol (12)(13)(14)(15)(16). Changes in intracellular pH activates autophagy (17,18).…”

mentioning

confidence: 99%

Intracellular pH Modulates Autophagy and Mitophagy

Berezhnov

Soutar

Fedotova

et al. 2016

Journal of Biological Chemistry

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“…Depletion of DJ-1, another Parkinson's-disease-associated gene, disrupts both mitochondrial dynamics and morphology (Hao et al, 2010;Irrcher et al, 2010;Thomas et al, 2011). In addition, two other Parkinson's-diseaseassociated proteins, F-box domain-containing protein (Fbxo7; also known as PARK15) and sterol regulatory element binding transcription factor (SREBF1) are also implicated in mitophagy (Burchell et al, 2013;Ivatt et al, 2014).…”

Section: Dynamics Of Mitochondrial Degradation In Neurodegenerative Dmentioning

confidence: 99%

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

116

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Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.

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“…Defects in mitochondrial quality control have been implicated in neurodegenerative conditions such as PD largely based on genetic mutations associated with familial, early onset forms of the disease. 2,3 In particular, there have been multiple associations between disease and mutations that disrupt a process called mitophagy, or the ability of damaged mitochondria to self-destruct. Mitophagy is a cellular quality control mechanism that selectively eliminates the damaged organelle and thereby protects the cell from death.…”

Section: All In the Familymentioning

confidence: 99%

“…a team of British researchers led in part by helene Plun-Favreau, a senior lecturer in the Department of molecular neuroscience at the UCL Institute of Neurology, recently reported that, similar to ParK2, FBXO7 plays a role in mitophagy downstream of PinK1. 3 "We are planning to do some compound screening in the near future to try and correct or improve mitophagy. One possibility would be to try to improve ParK2 and/or FBXO7 recruitment to damaged mitochondria," she said.…”

Section: All In the Familymentioning

confidence: 99%

All in the family

Donner¹

2013

Science-Business eXchange

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The Parkinson's disease–linked proteins Fbxo7 and Parkin interact to mediate mitophagy

Cited by 295 publications

References 46 publications

Intracellular pH Modulates Autophagy and Mitophagy

Intracellular pH Modulates Autophagy and Mitophagy

Autophagosome dynamics in neurodegeneration at a glance

All in the family

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