Mitophagy confers resistance to siderophore-mediated killing by
            <i>Pseudomonas aeruginosa</i>

Kirienko, Natalia V.; Ausubel, Frederick M.; Ruvkun, Gary

doi:10.1073/pnas.1424954112

Cited by 188 publications

(217 citation statements)

References 38 publications

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“…It has previously been shown that selection for nonproducers is expected to lower bacterial virulence (65,66). We observed that highly resistant producers also arose in mixed cultures, but they were outcompeted by resistant nonproducers.…”

Section: Discussionmentioning

confidence: 60%

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Vasse

Noble

Akhmetzhanov

et al. 2017

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

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Cheats are a pervasive threat to public goods production in natural and human communities, as they benefit from the commons without contributing to it. Although ecological antagonisms such as predation, parasitism, competition, and abiotic environmental stress play key roles in shaping population biology, it is unknown how such stresses generally affect the ability of cheats to undermine cooperation. We used theory and experiments to address this question in the pathogenic bacterium, Pseudomonas aeruginosa. Although public goods producers were selected against in all populations, our competition experiments showed that antibiotics significantly increased the advantage of nonproducers. Moreover, the dominance of nonproducers in mixed cultures was associated with higher resistance to antibiotics than in either monoculture. Mathematical modeling indicates that accentuated costs to producer phenotypes underlie the observed patterns. Mathematical analysis further shows how these patterns should generalize to other taxa with public goods behaviors. Our findings suggest that explaining the maintenance of cooperative public goods behaviors in certain natural systems will be more challenging than previously thought. Our results also have specific implications for the control of pathogenic bacteria using antibiotics and for understanding natural bacterial ecosystems, where subinhibitory concentrations of antimicrobials frequently occur.evolution | cooperation | antibiotics | social behavior | resistance P ublic goods production is a characteristic of a diverse range of taxa, from microbes to humans (1-3). Explaining the persistence of this costly behavior is challenging, because cheats can exploit the commons without contributing. Kin selection theory has proven to be a successful framework for addressing this question, with the central prediction that cooperation is favored by sufficient benefits to, and positive assortment between, cooperators (4-8). For example, recent study in experimental bacterial populations has elucidated mechanisms such as assortment emerging from limited or budding dispersal (9, 10) and kin discrimination (11, 12) that are consistent with kin selection fostering cooperative behaviors (e.g., refs. 8 and 13). However, despite this accumulating consensus, little is known about how social populations respond to differences and variation in abiotic and biotic components of their environment. In particular, it is unclear how ecological antagonisms affect the ability of cheats to invade cooperator communities.Cooperation can be affected by stress directly through differential selection on cooperative phenotypes (14, 15), or by inducing specific plastic behaviors (16-22), especially when cooperation leads to increased stress resistance. However, in the absence of a direct benefit of the cooperative behavior against stress, the ecological and evolutionary outcomes of the interactions between nondefensive public goods and stress responses are less clear and are potentially complex. Cooperation may be infl...

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Section: Discussionmentioning

confidence: 60%

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Vasse

Noble

Akhmetzhanov

et al. 2017

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

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“…Interestingly, while we were working on this paper, it was shown that iron chelators can induce mitophagy in mammalian cells [48] and in C. elegans [49], possibly as a way of recycling iron from the mitochondrial storage. These findings insinuate that, although frataxin silencing can induce mitophagy via cytosolic iron deprivation, the non-additive effects of the two combined treatments could also be a consequence of iron depletion-induced mitochondrial damage.…”

Section: Discussionmentioning

confidence: 96%

Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans

et al. 2015

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Frataxin is a nuclear-encoded mitochondrial protein involved in the biogenesis of Fe-S-cluster-containing proteins and consequently in the functionality of the mitochondrial respiratory chain. Similar to other proteins that regulate mitochondrial respiration, severe frataxin deficiency leads to pathology in humans--Friedreich's ataxia, a life-threatening neurodegenerative disorder--and to developmental arrest in the nematode C. elegans. Interestingly, partial frataxin depletion extends C. elegans lifespan, and a similar anti-aging effect is prompted by reduced expression of other mitochondrial regulatory proteins from yeast to mammals. The beneficial adaptive responses to mild mitochondrial stress are still largely unknown and, if characterized, may suggest novel potential targets for the treatment of human mitochondria-associated, age-related disorders. Here we identify mitochondrial autophagy as an evolutionarily conserved response to frataxin silencing, and show for the first time that, similar to mammals, mitophagy is activated in C. elegans in response to mitochondrial stress in a pdr-1/Parkin-, pink-1/Pink-, and dct-1/Bnip3-dependent manner. The induction of mitophagy is part of a hypoxia-like, iron starvation response triggered upon frataxin depletion and causally involved in animal lifespan extension. We also identify non-overlapping hif-1 upstream (HIF-1-prolyl-hydroxylase) and downstream (globins) regulatory genes mediating lifespan extension upon frataxin and iron depletion. Our findings indicate that mitophagy induction is part of an adaptive iron starvation response induced as a protective mechanism against mitochondrial stress, thus suggesting novel potential therapeutic strategies for the treatment of mitochondrial-associated, age-related disorders.

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“…67 However, Phen is unable to exert similar effects in neuronal-like SH-SY5Y cells, suggesting that its mitophagic activity might be cell type dependent. 68 In addition, the structurally similar siderophore 2'2-bipyridyl was shown to extend lifespan in C. elegans by inducing a mitophagic response that was dependent on PINK1 as well as PBR-1 and DCT-1, the C. elegans homologues of Parkin and NIX1/BNIP3 respectively ( Table 1 and Figure 5b).…”

Section: Iron Chelatorsmentioning

confidence: 99%

The pharmacological regulation of cellular mitophagy

2017

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Small molecules are pharmacological tools of considerable value in dissecting complex biological processes and identifying potential therapeutic interventions.Recently, the cellular quality control process of mitophagy attracted considerable research interest, however, the limited availability of suitable chemical probes restricted our understanding of the molecular mechanisms involved.Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (e.g. FCCP/CCCP), or the use of Antimycin A/Oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis, and therefore limit the scope for dissection of subtle, bio-energy related regulatory phenomena.Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation.We have therefore summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications.

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Mitophagy confers resistance to siderophore-mediated killing by Pseudomonas aeruginosa

Cited by 188 publications

References 38 publications

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa

Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans

The pharmacological regulation of cellular mitophagy

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