Mitochondrial SKN-1/Nrf Mediates a Conserved Starvation Response

Paek, Jennifer; Lo, Jacqueline Y.; Narasimhan, Sri Devi; Nguyen, Tammy N.; Glover-Cutter, Kira; Robida-Stubbs, Stacey; Suzuki, Takafumi; Yamamoto, Masayuki; Blackwell, T. Keith; Curran, Sean P.

doi:10.1016/j.cmet.2012.09.007

Cited by 160 publications

(205 citation statements)

References 51 publications

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“…We discovered that well-fed skn-1 gain-of-function mutant worms upregulated a large number of FAO genes (Fig. 3a), which is consistent with our previous observation that ad libitum-fed skn-1 gain-offunction animals behave as if they are starved 9 . Intriguingly, some FAO genes were found to be downregulated in skn-1 gain-offunction mutants as compared with wild-type controls (Fig.…”

Section: Skn-1 Protects Against Diet-induced Fat Accumulationsupporting

confidence: 79%

“…A role for the transcription factor SKN-1 has been documented under conditions of oxidative stress 4 and lifespan extension [5][6][7][8] , where nutrient availability is either perceived as reduced or is actually reduced. Furthermore, we recently found that gain-offunction mutations in skn-1 induce a starvation-like state 9 . As such, we proposed that a SKN-1-mediated transcriptional programme could mechanistically link proline and fatty acid metabolism.…”

Section: Skn-1 Mediates Lipid Metabolism Responses In Alh-6 Mutantsmentioning

confidence: 99%

“…In addition, SKN-1 is a well-known longevity factor that is activated in many long-lived mutant backgrounds with altered metabolic homeostasis and is indispensable for the lifespan extension of those mutants [5][6][7][8] . Recently, we reported that gain-of-function mutations in skn-1 lead to a starvation-like status in C. elegans and induce the expression of several metabolic genes 9 ; however, the full extent to which SKN-1 participates in organismal physiology and metabolism remains unknown.…”

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confidence: 99%

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SKN-1 and Nrf2 Couples Proline Catabolism With Lipid Metabolism During Nutrient Deprivation

2015

The Gerontologist

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Mechanisms that coordinate different metabolic pathways, such as glucose and lipid, have been recognized. However, a potential interaction between amino acid and lipid metabolism remains largely elusive. Here we show that during starvation of Caenorhabditis elegans, proline catabolism is coupled with lipid metabolism by SKN-1. Mutation of alh-6, a conserved proline catabolic enzyme, accelerates fat mobilization, enhances the expression of genes involved in fatty acid oxidation and reduces survival in response to fasting. This metabolic coordination is mediated by the activation of the transcription factor SKN-1/Nrf2, possibly due to the accumulation of the alh-6 substrate P5C, and also requires the transcriptional co-regulator MDT-15. Constitutive activation of SKN-1 induces a similar transcriptional response, which protects animals from fat accumulation when fed a high carbohydrate diet. In human cells, an orthologous alh-6 enzyme, ALDH4A1, is also linked to the activity of Nrf2, the human orthologue of SKN-1, and regulates the expression of lipid metabolic genes. Our findings identify a link between proline catabolism and lipid metabolism, and uncover a physiological role for SKN-1 in metabolism.

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Section: Skn-1 Protects Against Diet-induced Fat Accumulationsupporting

confidence: 79%

Section: Skn-1 Mediates Lipid Metabolism Responses In Alh-6 Mutantsmentioning

confidence: 99%

mentioning

confidence: 99%

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SKN-1 and Nrf2 Couples Proline Catabolism With Lipid Metabolism During Nutrient Deprivation

2015

The Gerontologist

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“…S3A). Mianserin did not further increase the stress resistance in the gain‐of‐function mutant skn‐1(lax188) (Paek et al ., 2012) that is already highly resistant to oxidative stress (Fig. S3B), suggesting SKN‐1 is involved in the protective mechanism.…”

Section: Resultsmentioning

confidence: 98%

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

et al. 2015

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SummaryOxidative stress has long been associated with aging and has recently been linked to psychiatric disorders, including psychosis and depression. We identified multiple antipsychotics and antidepressants that extend Caenorhabditis elegans lifespan and protect the animal from oxidative stress. Here, we report that atypical antidepressants activate a neuronal mechanism that regulates the response to oxidative stress throughout the animal. While the activation of the oxidative stress response by atypical antidepressants depends on synaptic transmission, the activation by reactive oxygen species does not. Lifespan extension by atypical antidepressants depends on the neuronal oxidative stress response activation mechanism. Neuronal regulation of the oxidative stress response is likely to have evolved as a survival mechanism to protect the organism from oxidative stress, upon detection of adverse or dangerous conditions by the nervous system.

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“…17 SKN-1 was also found to interact with the outer mitochondrial protein PGAM-5. 18 Calcium signalling modulates mitochondrial biogenesis through the calcium/calmodulin-dependent protein kinase II (CaMKII), p38 mitogen activated protein kinase (MAPK) and PGC-1α. 19,20 Although, no clear PGC-1a homolog is present in the nematode genome, we found that SKN-1 activity is modulated by cytoplasmic calcium levels via the CaMKII homolog, UNC-43, upon mitochondrial dysfunction.…”

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confidence: 99%

Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis

2015

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Mitochondria, the main energy hub of the cell, are highly dynamic organelles, playing essential roles in fundamental cellular processes. Mitochondrial function impinges on several signalling pathways modulating cellular metabolism, cell survival and healthspan. Accordingly, impairment of mitochondria has been associated with numerous pathological conditions and ageing. Maintenance of cellular and organismal homeostasis thus hinges on fine-tuning mitochondrial quality control. Mitochondrial biogenesis and mitochondrial selective autophagy (mitophagy), two opposing cellular pathways, coordinately regulate mitochondrial content to sustain energy metabolism, in response to cellular metabolic state, stress and other intracellular or environmental signals. It is not surprising, therefore, that disequilibrium or imbalance between mitochondrial proliferation and degradation processes underlies the onset and progressive unfolding of several pathological conditions in humans, including neurodegenerative diseases, myopathies and other age-associated disorders.Mitochondrial biogenesis is a complex and multistep cellular process, which involves mtDNA transcription and translation, translation of transcripts derived from nucleus, recruitment of newly synthesized proteins and lipids, import and assembly of mitochondrial and nuclear products in the expanding mitochondrial network. Spatiotemporal control of mitochondrial biogenesis is mediated by numerous transcription factors in response to diverse stimuli, including both intracellular signals and environmental stimuli (nutrient availability, growth factors and hormones, toxins, temperature and oxygen fluctuations, among others). The master regulator of mitochondrial energy metabolism is the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), the best-studied member of the peroxisome proliferator activated receptor family of transcription co-activators, which orchestrates the activity of several transcription factors involved in mitochondrial biogenesis and function. 1 These include the nuclear respiratory factors (NRF1 and NRF2), the estrogen-related receptors (ERR-α, -β and -γ) and the nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) that are part of a complex transcriptional network that regulates mitochondrial biogenesis and energy metabolism. 1,2 Alongside their essential roles in cell and animal physiology, mitochondria are also the major source of potentially hazardous reactive oxygen species as by-products of respiration. Thus, eukaryotic cells have evolved a wide arsenal of quality control mechanisms to preserve mitochondrial homeostasis and prevent cellular damage and eventual death. Mitophagy, a selective type of autophagy, is triggered upon accumulation of damaged or superfluous mitochondria. Dysfunctional mitochondria are targeted and engulfed by double-membrane vesicles known as autophagosomes and are transferred for degradation in lysosomes. Cells induce mitophagy to regulate the size and quality of their mitochondrial network...

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Mitochondrial SKN-1/Nrf Mediates a Conserved Starvation Response

Cited by 160 publications

References 51 publications

SKN-1 and Nrf2 Couples Proline Catabolism With Lipid Metabolism During Nutrient Deprivation

SKN-1 and Nrf2 Couples Proline Catabolism With Lipid Metabolism During Nutrient Deprivation

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis

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