Coupling mitogenesis and mitophagy for longevity

Palikaras, Konstantinos; Lionaki, Eirini; Tavernarakis, Nektarios

doi:10.1080/15548627.2015.1061172

Cited by 71 publications

(84 citation statements)

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“…Similar to the daf-16 , rict-1 , rsks-1, raga-1 and eat-2 mutants (Figure 3), the hypoxia-inducible factor mutant, hif-1(ia4) (Leiser and Kaeberlein, 2010), the NRF2 mutant, skn-1(zu135) (Tullet et al, 2008), and the mitophagy mutant, pink-1(ok3538) (Palikaras et al, 2015) all exhibit significant lifespan extension induced by Δlon ( p<0.001 , Figure 7A, Table S6), suggesting their negligible roles in regulating CA-induced longevity. In contrast, the Δlon bacterial mutant was unable to further prolong the lifespan of the nuo-6(qm200) or isp-1(qm150) C. elegans mutants (Figure 7A, Table S6), neither did the CA supplementation (Figure 7B and C, Table S7).…”

Section: Resultsmentioning

confidence: 63%

Microbial Genetic Composition Tunes Host Longevity

Han

Sivaramakrishnan

Lin

et al. 2017

Cell

257

184

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Summary Homeostasis of the gut microbiota critically influences host health and aging. Developing genetically engineered probiotics holds great promise as a new therapeutic paradigm to promote healthy aging. Here, through screening 3,983 Escherichia coli mutants, we discovered that 29 bacterial genes, when deleted, increase longevity in the host Caenorhabditis elegans. A dozen of these bacterial mutants also protect the host from age-related progression of tumor growth and amyloid-beta accumulation. Mechanistically, we discovered that five bacterial mutants promote longevity through increased secretion of the polysaccharide colanic acid (CA), which regulates mitochondrial dynamics and unfolded protein response (UPRmt) in the host. Purified CA polymers are sufficient to promote longevity via ATFS-1, the host UPRmt-responsive transcription factor. Furthermore, the mitochondrial changes and longevity effects induced by CA are conserved across different species. Together, our results identified molecular targets for developing pro-longevity microbes, and a bacterial metabolite acting on host mitochondria to promote longevity.

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Section: Resultsmentioning

confidence: 63%

Microbial Genetic Composition Tunes Host Longevity

Han

Sivaramakrishnan

Lin

et al. 2017

Cell

257

184

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“…When activated, SKN-1 transcribes a variety of gene targets that collectively act to restore cellular homeostasis. However, this can come with an energetic cost with pleiotropic consequences (An & Blackwell; Blackwell, Steinbaugh, Hourihan, Ewald, & Isik; Glover-Cutter, Lin, & Blackwell; Lynn et al; Paek et al; Palikaras, Lionaki, & Tavernarakis; Pang & Curran; Pang et al). alh-6 mutants have normal development, but display progeroid phenotypes towards the end of the normal reproductive span (Pang & Curran) indicating a temporal switch in phenotypic outcomes.…”

Section: Resultsmentioning

confidence: 99%

Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage inC. elegans

Yen

Ruter

Turner

et al. 2018

Preprint

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20Exposure to environmental stress is clinically established to influence male reproductive health, but the 21 impact of normal cellular metabolism on sperm quality is less well-defined. Here we show that impaired 22 mitochondrial proline catabolism, reduces energy-storing flavin adenine dinucleotide (FAD) levels, 23 alters mitochondrial dynamics toward fusion, and leads to age-related loss of sperm quality (size and 24 activity), which reduces competitive fitness. Loss of the 1-pyrroline-5-carboxylate dehydrogenase 25 enzyme alh-6 that catalyzes the second step in mitochondrial proline catabolism, leads to premature 26 male reproductive senescence. Reducing the expression of the proline catabolism enzyme alh-6 or 27 FAD biosynthesis pathway genes in the germline is sufficient to recapitulate the sperm-related 28 phenotypes observed in alh-6 loss-of-function mutants. These sperm-specific defects are suppressed 29 by feeding diets that restore FAD levels. Our results define a cell autonomous role for mitochondrial 30 proline catabolism and FAD homeostasis on sperm function and specify strategies to pharmacologically 31 reverse these defects.

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“…The observation that IGF-1 induces BNIP3 mRNA and protein expression and mitophagy could at first be considered somewhat surprising because BNIP3 can be induced by FOXO1, which is suppressed by IGF-1, and because nutrient deprivation is a well-described activator of mitophagy via suppressed TOR activity. There is, however, strong evidence for IGF signaling in supporting both mitochondrial biogenesis (PGC-1␤ and PRC) and turnover (BNIP3) from studies on longevity (40). SIRT1 has been reported to induce mitochondrial biogenesis by deacetylating and thus activating PGC-1␣ in times of nutrient deprivation (41) while also stimulating mitophagy (42).…”

Section: Igf-1 Signaling In Mitochondrial Protectionmentioning

confidence: 99%

Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells

Lyons¹,

Coleman²,

Riis³

et al. 2017

Journal of Biological Chemistry

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Mitochondrial activity and metabolic reprogramming influence the phenotype of cancer cells and resistance to targeted therapy. We previously established that an insulin-like growth factor 1 (IGF-1)-inducible mitochondrial UTP carrier (PNC1/SLC25A33) promotes cell growth. This prompted us to investigate whether IGF signaling is essential for mitochondrial maintenance in cancer cells and whether this contributes to therapy resistance. Here we show that IGF-1 stimulates mitochondrial biogenesis in a range of cell lines. In MCF-7 and ZR75.1 breast cancer cells, IGF-1 induces peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) and PGC-1α-related coactivator (PRC). Suppression of PGC-1β and PRC with siRNA reverses the effects of IGF-1 and disrupts mitochondrial morphology and membrane potential. IGF-1 also induced expression of the redox regulator nuclear factor-erythroid-derived 2-like 2 (NFE2L2 alias NRF-2). Of note, MCF-7 cells with acquired resistance to an IGF-1 receptor (IGF-1R) tyrosine kinase inhibitor exhibited reduced expression of PGC-1β, PRC, and mitochondrial biogenesis. Interestingly, these cells exhibited mitochondrial dysfunction, indicated by reactive oxygen species expression, reduced expression of the mitophagy mediators BNIP3 and BNIP3L, and impaired mitophagy. In agreement with this, IGF-1 robustly induced BNIP3 accumulation in mitochondria. Other active receptor tyrosine kinases could not compensate for reduced IGF-1R activity in mitochondrial protection, and MCF-7 cells with suppressed IGF-1R activity became highly dependent on glycolysis for survival. We conclude that IGF-1 signaling is essential for sustaining cancer cell viability by stimulating both mitochondrial biogenesis and turnover through BNIP3 induction. This core mitochondrial protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer.

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Coupling mitogenesis and mitophagy for longevity

Cited by 71 publications

References 0 publications

Microbial Genetic Composition Tunes Host Longevity

Microbial Genetic Composition Tunes Host Longevity

Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage inC. elegans

Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells

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