Mitonuclear protein imbalance as a conserved longevity mechanism

Houtkooper, Riekelt H.; Mouchiroud, Laurent; Ryu, Dongryeol; Moullan, Norman; Katsyuba, Elena; Knott, Graham; Williams, Robert W.; Auwerx, Johan

doi:10.1038/nature12188

Cited by 908 publications

(1,179 citation statements)

References 47 publications

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“…Interestingly, these interventions were then found to trigger the mitochondrial unfolded protein response (UPR mit ) that contributes to the observed lifespan extension (Durieux, Wolff, & Dillin, 2011). Similar observations were also described in mice (Houtkooper et al, 2013; Jovaisaite, Mouchiroud, & Auwerx, 2014). …”

Section: Resultssupporting

confidence: 85%

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

et al. 2018

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Plant extracts containing salicylates are probably the most ancient remedies to reduce fever and ease aches of all kind. Recently, it has been shown that salicylates activate adenosine monophosphate‐activated kinase (AMPK), which is now considered as a promising target to slow down aging and prevent age‐related diseases in humans. Beneficial effects of AMPK activation on lifespan have been discovered in the model organism Caenorhabditis elegans (C. elegans). Indeed, salicylic acid and acetylsalicylic acid extend lifespan in worms by activating AMPK and the forkhead transcription factor DAF‐16/FOXO. Here, we investigated whether another salicylic acid derivative 5‐octanoyl salicylic acid (C8‐SA), developed as a controlled skin exfoliating ingredient, had similar properties using C. elegans as a model. We show that C8‐SA increases lifespan of C. elegans and that a variety of pathways and genes are required for C8‐SA‐mediated lifespan extension. C8‐SA activates AMPK and inhibits TOR both in nematodes and in primary human keratinocytes. We also show that C8‐SA can induce both autophagy and the mitochondrial unfolded protein response (UPRmit) in nematodes. This induction of both processes is fully required for lifespan extension in the worm. In addition, we found that the activation of autophagy by C8‐SA fails to occur in worms with compromised UPRmit, suggesting a mechanistic link between these two processes. Mutants that are defective in the mitochondrial unfolded protein response exhibit constitutive high autophagy levels. Taken together, these data therefore suggest that C8‐SA positively impacts longevity in worms through induction of autophagy and the UPRmit.

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Section: Resultssupporting

confidence: 85%

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

et al. 2018

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“…Doxycycline was obtained from Sigma-Aldrich and dissolved in water 23 . For experiments, a final concentration of 15 μg/mL was used.…”

Section: Methodsmentioning

confidence: 99%

“…Given the tight link between the UPR mt and AD observed above, we investigated the effects of two established strategies to induce the UPR mt in C. elegans ; genetically, by silencing the expression of the mitochondrial ribosomal protein mrps-5 23 , and pharmacologically, by using the mitochondrial translation inhibitor doxycycline (dox) 23,24 . Both interventions, which favor worm health and lifespan 23 , markedly induced transcripts of UPR mt , mitophagy and respiration genes in GMC101 (Fig.…”

Section: Reducing Mitochondrial Translation Lowers Aβ Proteotoxicitymentioning

confidence: 99%

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Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

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Alzheimer’s disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.

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“…However, using the CNV approach, we found that the majority of complex I members do not change significantly relative to the rest of mitochondrial proteins (Fig 3D, right panels, and Dataset EV6). We instead revealed two members of the complex I (the nuclear‐encoded NDUF‐2.2 and the mitochondrial‐encoded ND5) that showed extreme and opposite CNV values, suggesting loss of stoichiometry due to mitonuclear imbalance (Fig 3E; Houtkooper et al , 2013). Similarly, the abundance of mitochondrial ribosome components was suggested to be decreasing with age.…”

Section: Resultsmentioning

confidence: 84%

Quantifying compartment‐associated variations of protein abundance in proteomics data

Parca

Beck

Bork

et al. 2018

Molecular Systems Biology

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Quantitative mass spectrometry enables to monitor the abundance of thousands of proteins across biological conditions. Currently, most data analysis approaches rely on the assumption that the majority of the observed proteins remain unchanged across compared samples. Thus, gross morphological differences between cell states, deriving from, e.g., differences in size or number of organelles, are often not taken into account. Here, we analyzed multiple published datasets and frequently observed that proteins associated with a particular cellular compartment collectively increase or decrease in their abundance between conditions tested. We show that such effects, arising from underlying morphological differences, can skew the outcome of differential expression analysis. We propose a method to detect and normalize morphological effects underlying proteomics data. We demonstrate the applicability of our method to different datasets and biological questions including the analysis of sub‐cellular proteomes in the context of Caenorhabditis elegans aging. Our method provides a complementary perspective to classical differential expression analysis and enables to uncouple overall abundance changes from stoichiometric variations within defined group of proteins.

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Mitonuclear protein imbalance as a conserved longevity mechanism

Cited by 908 publications

References 47 publications

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Quantifying compartment‐associated variations of protein abundance in proteomics data

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