Neuroprotective coordination of cell mitophagy by the ATPase Inhibitory Factor 1

Matić, Ivana Z.; Cocco, Stefania; Ferraina, Caterina; Martín-Jiménez, Rebeca; Florenzano, Fulvio; Crosby, James; Lupi, Ramona; Amadoro, Giuseppina; Russell, Claire; Pignataro, Giuseppe; Annunziato, Lucio; Abramov, Andrey Y.; Campanella, Michelangelo

doi:10.1016/j.phrs.2015.10.010

Cited by 23 publications

(23 citation statements)

References 71 publications

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“…For instance, NIX/BNIP3L mediates mitochondrial removal during cerebral 28 and cardiac 29 ischaemia/reperfusion (I/R) injury; also, FUNDC1 is a well-known regulator of mitophagy under hypoxia 11 , and its implications in ischaemia have been recently elucidated 30 , 31 . Of note, the intramitochondrial protein ATPIF1, during ischaemia-preconditioning context, has been reported to regulate selective degradation of potentially toxic mitochondria (i.e., those generating high doses of free radicals) by collapsing their membrane potential (ΔΨm) 32 , 33 .…”

Section: Resultsmentioning

confidence: 99%

“…We thus tested the degree of AMBRA1 phosphorylation in SH-SY5Y cells exposed to an in vitro model of ischaemia mimicked by alternative time periods of oxygen-glucose deprivation/re-oxygenation (OGD/RX) 33 . Total lysates were then subjected to western blot analysis of P-S1014-AMBRA1, recording that AMBRA1 is neatly phosphorylated between 30 min and 1 h of OGD/RX treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, cells were exposed to 1 h of OGD. Initially, OGD was performed in a medium previously satured with 95% N 2 and 5% CO 2 for 20 min and containing NaCl 116 mM, KCl 5.4 mM, MgSO 4 0.8 mM, NaHCO 3 26.2 mM, NaH 2 PO 4 1 mM, CaCl 2 1.8 mM, glycine 0.001 mM and 0.001 w/v phenol red 33 , 70 . Then, hypoxic conditions were maintained using a hypoxia chamber at 37 °C, 5% CO 2 and 95% N 2 .…”

Section: Methodsmentioning

confidence: 99%

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HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα

Rita¹,

Peschiaroli²,

Dâ2Acunzo³

et al. 2018

Nat Commun

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195

175

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The selective removal of undesired or damaged mitochondria by autophagy, known as mitophagy, is crucial for cellular homoeostasis, and prevents tumour diffusion, neurodegeneration and ageing. The pro-autophagic molecule AMBRA1 (autophagy/beclin-1 regulator-1) has been defined as a novel regulator of mitophagy in both PINK1/PARKIN-dependent and -independent systems. Here, we identified the E3 ubiquitin ligase HUWE1 as a key inducing factor in AMBRA1-mediated mitophagy, a process that takes place independently of the main mitophagy receptors. Furthermore, we show that mitophagy function of AMBRA1 is post-translationally controlled, upon HUWE1 activity, by a positive phosphorylation on its serine 1014. This modification is mediated by the IKKα kinase and induces structural changes in AMBRA1, thus promoting its interaction with LC3/GABARAP (mATG8) proteins and its mitophagic activity. Altogether, these results demonstrate that AMBRA1 regulates mitophagy through a novel pathway, in which HUWE1 and IKKα are key factors, shedding new lights on the regulation of mitochondrial quality control and homoeostasis in mammalian cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα

Rita¹,

Peschiaroli²,

Dâ2Acunzo³

et al. 2018

Nat Commun

Self Cite

195

175

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show abstract

“…These conditions are predicted to facilitate mutant mtDNA maintenance or accumulation555657. Similarly, levels of ATPIF1 may primarily reflect the need to buffer mitochondrial membrane potential from transient changes associated with muscle contraction and/or mediate metabolic reprogramming and responses to stress66. PINK1 and Parkin also play a number of non-mitophagic roles in Drosophila and mammalian systems, which may be costly if activated continuously676869.…”

Section: Discussionmentioning

confidence: 99%

Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila

et al. 2016

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Mitochondrial DNA (mtDNA) often exists in a state of heteroplasmy, in which mutant mtDNA co-exists in cells with wild-type mtDNA. High frequencies of pathogenic mtDNA result in maternally inherited diseases; maternally and somatically acquired mutations also accumulate over time and contribute to diseases of ageing. Reducing heteroplasmy is therefore a therapeutic goal and in vivo models in post-mitotic tissues are needed to facilitate these studies. Here we describe a transgene-based model of a heteroplasmic lethal mtDNA deletion (mtDNAΔ) in adult Drosophila muscle. Stimulation of autophagy, activation of the PINK1/parkin pathway or decreased levels of mitofusin result in a selective decrease in mtDNAΔ. Decreased levels of mitofusin and increased levels of ATPIF1, an inhibitor of ATP synthase reversal-dependent mitochondrial repolarization, result in a further decrease in mtDNAΔ levels. These results show that an adult post-mitotic tissue can be cleansed of a deleterious genome, suggesting that therapeutic removal of mutant mtDNA can be achieved.

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“…Additionally, molecular regulators of mitochondrial bioenergy during stress conditions have been recently reported to play part in this process. For examplethe overexpesssion and activation of ATPIF1, the endogenous ATPase inhibitor, is essential to induce mitochondrial accumulation of of PINK1 (Lefebvre et al, 2013;Matic et al, 2016).…”

Section: Molecular Physiology Of Mitochondrial Quality Controlmentioning

confidence: 99%

Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection

East

Campanella

2016

The International Journal of Biochemistry & Cell Biology

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Neuroprotective coordination of cell mitophagy by the ATPase Inhibitory Factor 1

Cited by 23 publications

References 71 publications

HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα

HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα

Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila

Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection

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