Gkikas, I. et al. (2019) International Worm Meeting "Mitochondrial function and HIF-1- independent organismal survival under hypoxia."

Daskalaki, I., Gkikas, I., Lionaki, E., Tavernarakis, N.

[International Worm Meeting, 2019]

Oxygen deficiency, referred to as hypoxia, entails substantial reprogramming of mitochondrial metabolism to meet energy requirements. As such, reduction of mitochondrial efficiency and enhancement of glycolytic metabolism are commonly observed in hypoxic cells. This adaptation is attributed mostly to the activity of hypoxia-inducible factor 1 (HIF-1), as our knowledge on HIF-1-independent responses remains obscure. Here, we show that mitochondrial function is more prevalent than or act in parallel to glycolysis even under conditions of hypoxia. Challenging the prevailing notion, we show that maintenance of mitochondrial function is sufficient to promote survival of hypoxic cells independently of HIF-1. Importantly, we uncover a noncanonical role of E2F/EFL-1 transcription factor in mitochondrial metabolism. Under hypoxia, EFL-1 overrides HIF-1 activity on mitochondria. Particularly, EFL-1 controls the expression of hypoxia-responsive genes involved in oxidative phosphorylation, TCA cycle and glycolysis. Interestingly, we found that loss of the EFL-1 target TRIAP1/MDMH-35, increases mitochondrial cardiolipin levels and mitochondrial bioenergetics in response to oxygen deprivation. We propose that the EFL-1/MDMH-35 axis controls mitochondrial cardiolipin biosynthesis independent of HIF-1 to determine hypoxic cell survival and/or death.

Gkikas, I. et al. (2017) International Worm Meeting "HIF-1-independent hypoxic resistance involves a novel mechanism of mitochondrial adaptation in C. elegans."

Tavernarakis, N., Gkikas, I., Lionaki, E., Daskalaki, I.

[International Worm Meeting, 2017]

Oxygen deprivation (hypoxia) is a key feature of several common and devastating disorders including stroke, ischemic heart disease and cancer. Survival under hypoxia requires activation of various hypoxia-responsive genes, involved in mitochondrial function, glucose metabolism, glycolysis, autophagy, the unfolded protein response (UPR) and apoptosis. Although the hypoxia-inducible factor-1 (HIF-1) is an essential transcription factor coordinating many of these transcriptional responses, HIF-1-independent hypoxia-responses also occur. The complex regulatory network engaged upon hypoxia, independently of HIF-1, is not fully understood. We uncovered a HIF-1-independent hypoxia response mechanism which involves the C. elegans homolog of the mammalian TRIAP1/p53CSV, T09A5.7/TRIAP-1, and mitochondrial metabolic adaptation. Notably, knock-down of TRIAP-1 promotes organismal survival under conditions of prolonged hypoxia, in the absence of HIF-1. In addition, TRIAP-1 depletion induces mitochondrial metabolic adaptation upon hypoxia. We find that TRIAP-1 is required for the proper function of key stress response pathways including autophagy, UPR and the intrinsic apoptotic pathway. Taken together, our findings indicate that TRIAP-1 plays an important role for in organismal adaptation to hypoxia that is independent of HIF-1.

Gkikas I et al. (2023) Int J Mol Sci "MitoSNARE Assembly and Disassembly Factors Regulate Basal Autophagy and Aging in C. elegans."

Lionaki E, Tavernarakis N, Gkikas I, Kounakis K, Daskalaki I

[Int J Mol Sci, 2023]

SNARE proteins reside between opposing membranes and facilitate vesicle fusion, a physiological process ubiquitously required for secretion, endocytosis and autophagy. With age, neurosecretory SNARE activity drops and is pertinent to age-associated neurological disorders. Despite the importance of SNARE complex assembly and disassembly in membrane fusion, their diverse localization hinders the complete understanding of their function. Here, we revealed a subset of SNARE proteins, the syntaxin SYX-17, the synaptobrevins VAMP-7, SNB-6 and the tethering factor USO-1, to be either localized or in close proximity to mitochondria, in vivo. We term them mitoSNAREs and show that animals deficient in mitoSNAREs exhibit increased mitochondria mass and accumulation of autophagosomes. The SNARE disassembly factor NSF-1 seems to be required for the effects of mitoSNARE depletion. Moreover, we find mitoSNAREs to be indispensable for normal aging in both neuronal and non-neuronal tissues. Overall, we uncover a previously unrecognized subset of SNAREs that localize to mitochondria and propose a role of mitoSNARE assembly and disassembly factors in basal autophagy regulation and aging.

Souza ACR et al. (2018) Genes (Basel) "Pathogenesis of the Candida parapsilosis Complex in the Model Host Caenorhabditis elegans."

Colombo AL, Fuchs BB, Jayamani E, Mylonakis E, Souza ACR, Alves VS

[Genes (Basel), 2018]

<i>Caenorhabditis</i><i>elegans</i> is a valuable tool as an infection model toward the study of <i>Candida</i> species. In this work, we endeavored to develop a <i>C</i>. <i>elegans</i>-<i>Candida</i><i>parapsilosis</i> infection model by using the fungi as a food source. Three species of the C. parapsilosis complex (<i>C.</i><i>parapsilosis</i> (<i>sensu</i><i>stricto</i>), <i>Candida</i><i>orthopsilosis</i> and <i>Candida</i><i>metapsilosis</i>) caused infection resulting in <i>C. elegans</i> killing. All three strains that comprised the complex significantly diminished the nematode lifespan, indicating the virulence of the pathogens against the host. The infection process included invasion of the intestine and vulva which resulted in organ protrusion and hyphae formation. Importantly, hyphae formation at the vulva opening was not previously reported in <i>C</i>. <i>elegans</i>-<i>Candida</i> infections. Fungal infected worms in the liquid assay were susceptible to fluconazole and caspofungin and could be found to mount an immune response mediated through increased expression of <i>cnc</i>-<i>4</i>, <i>cnc</i>-<i>7</i>, and <i>fipr</i><i>-</i><i>22</i>/<i>23</i>. Overall, the <i>C</i>. <i>elegans</i>-<i>C</i>. <i>parapsilosis</i> infection model can be used to model <i>C</i>. <i>parapsilosis</i> host-pathogen interactions.

Fourie R et al. (2021) Front Cell Infect Microbiol "Candida albicans SET3 Plays a Role in Early Biofilm Formation, Interaction With Pseudomonas aeruginosa and Virulence in Caenorhabditis elegans."

Sebolai O, Fourie R, Albertyn J, Pohl CH, Gcilitshana O

[Front Cell Infect Microbiol, 2021]

The yeast <i>Candida albicans</i> exhibits multiple morphologies dependent on environmental cues. <i>Candida albicans</i> biofilms are frequently polymicrobial, enabling interspecies interaction through proximity and contact. The interaction between <i>C. albicans</i> and the bacterium, <i>Pseudomonas aeruginosa</i>, is antagonistic <i>in vitro, with P. aeruginosa</i> repressing the yeast-to-hyphal switch in <i>C. albicans</i>. Previous transcriptional analysis of <i>C. albicans</i> in polymicrobial biofilms with <i>P. aeruginosa</i> revealed upregulation of genes involved in regulation of morphology and biofilm formation, including <i>SET3</i>, a component of the Set3/Hos2 histone deacetylase complex (Set3C). This prompted the question regarding the involvement of <i>SET3</i> in the interaction between <i>C. albicans</i> and <i>P. aeruginosa</i>, both <i>in vitro</i> and <i>in vivo.</i> We found that <i>SET3</i> may influence early biofilm formation by <i>C. albicans</i> and the interaction between <i>C. albicans</i> and <i>P. aeruginosa</i>. In addition, although deletion of <i>SET3</i> did not alter the morphology of <i>C. albicans</i> in the presence of <i>P. aeruginosa</i>, it did cause a reduction in virulence in a <i>Caenorhabditis elegans</i> infection model, even in the presence of <i>P. aeruginosa.</i>

Zhu Q et al. (2020) Oxid Med Cell Longev "A Dihydroflavonoid Naringin Extends the Lifespan of C. elegans and Delays the Progression of Aging-Related Diseases in PD/AD Models via DAF-16."

Zhou XG, Qu Y, Luo HR, Zhu Q, Wu GS, Chen JN

[Oxid Med Cell Longev, 2020]

Naringin is a dihydroflavonoid, which is rich in several plant species used for herbal medicine. It has a wide range of biological activities, including antineoplastic, anti-inflammatory, antiphotoaging, and antioxidative activities. So it would be interesting to know if naringin has an effect on aging and aging-related diseases. We examined the effect of naringin on the aging of <i>Caenorhabditis elegans</i> (<i>C</i>. <i>elegans</i>). Our results showed that naringin could extend the lifespan of <i>C</i>. <i>elegans</i>. Moreover, naringin could also increase the thermal and oxidative stress tolerance, reduce the accumulation of lipofuscin, and delay the progress of aging-related diseases in <i>C</i>. <i>elegans</i> models of AD and PD. Naringin could not significantly extend the lifespan of long-lived mutants from genes in insulin/IGF-1 signaling (IIS) and nutrient-sensing pathways, such as <i>daf</i>-<i>2</i>, <i>akt</i>-<i>2</i>, <i>akt</i>-<i>1</i>, <i>eat</i>-<i>2</i>, <i>sir</i>-<i>2</i>.<i>1</i>, and <i>rsks</i>-<i>1</i>. Naringin treatment prolonged the lifespan of long-lived <i>glp</i>-<i>1</i> mutants, which have decreased reproductive stem cells. Naringin could not extend the lifespan of a null mutant of the fox-head transcription factor DAF-16. Moreover, naringin could increase the mRNA expression of genes regulated by <i>daf</i>-<i>16</i> and itself. In conclusion, we show that a natural product naringin could extend the lifespan of <i>C</i>. <i>elegans</i> and delay the progression of aging-related diseases in <i>C</i>. <i>elegans</i> models via DAF-16.

Coomansingh-Springer C et al. (2019) Heliyon "Internal parasitic burdens in brown rats (Rattus norvegicus) from Grenada, West Indies."

Sharma RN, Armstrong E, Vishakha V, Acuna AM, Coomansingh-Springer C

[Heliyon, 2019]

This study identified the endoparasites in Brown rat (<i>Rattus norvegicus)</i> during May to July 2017 in Grenada, West Indies. A total of 162 rats, 76 females and 86 males were trapped from St. George and St. David parishes in Grenada. The collected fecal samples were examined for parasitic eggs and/or oocysts using simple fecal flotation technique. Adult parasites found in the intestinal tract were examined for identification. The overall prevalence of intestinal parasites among rats was 79 %. Ten helminth species were recovered, several of which were reported for the first time in rodents in Grenada. The internal parasites consist of seven nematodes (<i>Angiostrongylus</i> spp., <i>Nippostrongylus braziliensis</i>, <i>Heterakis spumosa</i>, <i>Strongyloides ratti</i>, <i>Aspiculuris tetraptera</i>, <i>Syphacia</i> spp. and <i>Protospirura</i> spp.), one cestode (<i>Hymenolepsis diminuta</i>), one acanthocephalan (<i>Moniliformis moniliformis</i>) and one protozoa species (<i>Eimeria</i> spp.). The most prevalent zoonotic species were <i>Angiostrongylus</i> spp. (35.2%), <i>Hymenolepsis diminuta</i> (7.4%) and <i>Moniliformis moniliformis</i> (3.1%). Several nonzoonotic endoparasites; which included <i>Nippostrongylus braziliensis</i> (50.6%), <i>Heterakis spumosa</i> (15.4%), <i>Strongyloides ratti</i> (43.2%), <i>Aspiculuris tetraptera</i> (2.5%), <i>Syphacia</i> spp<i>.</i> (1.9%), <i>Protospirura</i> spp. (1.2%) and <i>Eimeria</i> spp. (4.7%) were also identified. The most prevalent parasites were <i>Nippostrongylus brasiliensis</i> (50.6%), <i>Strongyloides ratti</i> (43.2%) and <i>Angiostrongylus spp.</i> (35.2%). Co-infections occurred with up to six species per rat showing different combinations of parasitic infections.

Wu CJ et al. (2019) Appl Environ Microbiol "Genotypic and Phenotypic Characteristics of Aeromonas Isolates from Fish and Patients in Tainan City."

Shu CY, Li CW, Ko WC, Su YC, Chen YW, Lee NY, Su SL, Wu CJ, Chen PL, Li MC, Lin YT

[Appl Environ Microbiol, 2019]

The present study aimed to isolate <i>Aeromonas</i> from fish sold in the markets as well as in sushi and seafood shops and compare their virulence factors and antimicrobial characteristics with those of clinical isolates. Among the 128 fish isolates and 47 clinical isolates, <i>A. caviae</i>, <i>A. dhakensis</i>, and <i>A. veronii</i> were the principal species. <i>A. dhakensis</i> isolates carried at least 5 virulence genes, more than other <i>Aeromonas</i> species. The predominant genotype of virulence genes was <i>hlyA/lip/alt/col/el</i> in both <i>A. dhakensis</i> and <i>A. hydrophila</i> isolates, <i>alt/col/ela</i> in <i>A. caviae</i> isolates, and <i>act</i> in <i>A. veronii</i> isolates. <i>A. dhakensis</i>, <i>A. hydrophila</i>, and <i>A. veronii</i> isolates more often exhibited hemolytic and proteolytic activity and showed greater virulence than <i>A. caviae</i> in <i>Caenorhabditis elegans</i> and the C2C12 cell line. However, the link between the genotypes and phenotypes of the studied virulence genes in <i>Aeromonas</i> species is not evident. Among the four major clinical <i>Aeromonas</i> species, nearly all (99.0%) <i>A. dhakensis</i>, <i>A. hydrophila</i>, and <i>A. veronii</i> isolates harbored <i>bla</i>_CphA, which encodes a carbapenemase, but only a minority (6.7%, 7/104) were nonsusceptible to carbapenem. Regarding AmpC -lactamase genes, <i>bla</i>_AQU-1 was exclusively found in <i>A. dhakensis</i> isolates and <i>bla</i>_MOX3 only in <i>A. caviae</i> isolates, but only 7.6% (6) of the 79 <i>Aeromonas</i> isolates carrying <i>bla</i>_AQU-1 or <i>bla</i>_MOX3 exhibited a cefotaxime resistance phenotype. In conclusion, fish <i>Aeromonas</i> isolates carry a variety of combinations of virulence and B-lactamase resistance genes and exhibit virulence phenotypes and antimicrobial resistance profiles similar to those of clinical isolates.<b>IMPORTANCE</b><i>Aeromonas</i> species can cause severe infections in immunocompromised individuals upon exposure to virulent pathogens in the environment, but the characteristics of environmental <i>Aeromonas</i> species remain unclear. Our study showed several pathogenic <i>Aeromonas</i> species possessing virulence traits and antimicrobial resistance similar to those of <i>Aeromonas</i> isolates causing clinical diseases were present in fish intended for human consumption in Tainan City.

Hariri S et al. (2023) MicroPubl Biol "53bp1 mutation enhances brca1 and bard1 embryonic lethality in C. elegans."

Engebrecht J, Hariri S, Li Q

[MicroPubl Biol, 2023]

In mice, mutation of <i>brca1</i> results in embryonic lethality, which is partially suppressed by <i>53bp1</i> mutation. In contrast, mutation of the <i>C. elegans</i> BRCA1 ortholog, <i>brc-1 ,</i> or its binding partner, <i>brd-1</i> , lead to only mild embryonic lethality. We show that in <i>C. elegans</i> , <i>brc-1</i> and <i>brd-1</i> embryonic lethality is enhanced when <i>53bp1</i> ortholog, <i>hsr-9</i> , is also mutated. This is not a consequence of activating <i>polq-1</i> -dependent microhomology-mediated end joining, as <i>polq-1</i> mutation does not suppress embryonic lethality of <i>hsr-9 ; brc-1</i> mutants. Together, these results suggest that BRC-1 - BRD-1 and HSR-9 function in parallel pathways and do not act antagonistically as in mammals.

Sun S et al. (2019) Biosci Microbiota Food Health "Toll-like receptor homolog TOL-1 regulates Bifidobacterium infantis-elicited longevity and behavior in Caenorhabditis elegans."

Komura T, Nishikawa Y, Mizuno Y, Kage-Nakadai E, Sun S

[Biosci Microbiota Food Health, 2019]

<i>Bifidobacterium infantis</i>, a Gram-positive bacterium, is one of the commonly used probiotics. We previously showed that <i>B. infantis</i> modified host defense systems and extended the lifespan of the nematode <i>Caenorhabditis elegans</i>. In the present study, we showed that the lifespan extension caused by <i>B. infantis</i> was enhanced in animals having a mutation in the <i>tol-1</i> gene that encodes the sole <i>C. elegans</i> homolog of Toll-like receptors (TLRs). Meanwhile, lifespan increased by other probiotic bacteria, such as <i>Bacillus subtilis</i> or <i>Clostridium butyricum</i>, was not affected in the <i>tol-1</i> mutant animals. A microarray analysis revealed that the expression of innate immune response-related genes was significantly increased in the <i>tol-1</i> mutant. Worms with the <i>tol-1</i> mutation exhibited reduced leaving behavior from the <i>B. infantis</i> lawn, while canonical downstream factors <i>trf-1</i>/TRAF and <i>ikb-1</i>/IB appeared to not be involved. In conclusion, <i>C. elegans tol-1</i>/TLR regulates <i>B. infantis</i>-induced longevity and also regulates behavior against <i>B. infantis</i>.