Mains PE (1994) Worm Breeder's Gazette "Interactions Between mei-1 and the unc-116 Kinesin"

Mains PE

[Worm Breeder's Gazette, 1994]

Interactions Between mei-l and the unc-116 Kinesin Paul E. Mains, Dept. of Medical Biochemistry, University of Calgary, Calgary, Alberta, Canada

Wissmann AK et al. (1994) Worm Breeder's Gazette "Characterization of the let-502 Gene"

Mains PE, Wissmann AK, McGhee JD

[Worm Breeder's Gazette, 1994]

Characterization of the let-502 gene Andreas Wissmann, James D. McGhee and Paul E. Mains, Dept. of Medical Biochemistry, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Sommer RJ et al. (1994) Worm Breeder's Gazette "Evolution of Vulva-Formation: Part II: Species With a Central Vulva"

Sommer RJ, Sternberg PW

[Worm Breeder's Gazette, 1994]

Evolution of vulva-formation: Part II: Species with a central vulva Ralf J. Sommer & Paul W. Sternberg, California Institute of Technology, Division of Biology 156-29, Pasadena, CA 91125

Li WQ et al. (1992) Worm Breeder's Gazette "Characterization of the Axonal Guidance and Outgrowth gene Unc-33"

Shaw JE, Li WQ, Herman RK

[Worm Breeder's Gazette, 1992]

Characterization of the axonal guidance and outgrowth gene unc-33 W. Li, R. K. Herman and J. E. Shaw Department of Genetics and Cell biology, University of Minnesota, St Paul, MN 55108

Sommer RJ et al. (1994) Worm Breeder's Gazette "Evolution of Vulva Formation: Part IV: Variation in AC Position Can Cause a Shift of Vulva Formation Towards P(4-6).p."

Sternberg PW, Sommer RJ

[Worm Breeder's Gazette, 1994]

Evolution of vulva formation: Part IV: Variation in AC position can cause a shift of vulva formation towards p(4- 6).p Ralf J. Sommer & Paul W. Sternberg, HHMI & California Institute of Technology, Division of Biology 156-29, Pasadena, CA

Pena, Salvador et al. (2015) International Worm Meeting "Hypoxia and the Mitochondrial Unfolded Protein Response."

Pena, Salvador, Sherman, Teresa, Brookes, Paul, Nehrke, Keith

[International Worm Meeting, 2015]

The mitochondrial unfolded protein response (UPRmt) is a surveillance pathway induced by diverse stressors including reactive oxygen species, respiratory chain deficits, and mitochondrial DNA damage. Its activation helps to restore proteostasis and to protect against stresses caused by statin toxicity and bacterial infection. The transcription factor ATFS-1 is required for UPRmt signaling and the balance between ATFS-1 trafficking to the mitochondria and the nucleus regulates its signaling output. Consistent with a central role for mitochondria in mammalian ischemia-reperfusion injury, we found that either pharmacological or genetic activation of the UPRmt was sufficient to protect worms from anoxic death and cell damage. We found that atfs-1 was necessary for this protection and that in the absence of atfs-1, mitochondrial stress exacerbated anoxic death. In contrast, a gain-of-function (gf) mutation in atfs-1 was endogenously protected against anoxia. We then created a genetic model to study the cell specific effects of atfs-1. Our model utilizes a FLP-FRT-wCherry promoter interruption of an atfs-1 single copy MosSCI transgene to restrict the expression of either the wild type or gf allele to specific cells. Expression in this model via the native promoter at physiological levels is expected to more closely recapitulate endogenous regulatory mechanisms. Since mitochondrial stress has been suggested to result in non-cell autonomous signaling, we were motivated to use our model to determine whether the UPRmt could also protect cells from anoxic damage through similar mechanisms. We tested whether selective expression of atfs-1 was sufficient to activate the UPRmt in specific tissues and whether this elicited global adaptation to anoxia. In addition to allowing us to rigorously define the role of atfs-1 in regulating anoxic sensitivity, this model will be useful in studying how UPRmt influences other cellular and systems outputs.

Wojtovich, Andrew et al. (2015) International Worm Meeting "Chromophore-assisted light inactivation of mitochondrial respiratory chain complex II in C. elegans using a miniSOG mev-1 fusion."

Wojtovich, Andrew, Nehrke, Keith, Brookes, Paul, Foster, Thomas, Sherman, Teresa

[International Worm Meeting, 2015]

Mitochondria play a critical role in meeting cellular energy demand and are implicated in cell death, stress responses and reactive oxygen species (ROS) signaling. Respiratory complex II occupies a unique position within the mitochondrial metabolism machinery, being both a component of the electron transport chain and the Krebs cycle. Moreover, all four subunits of complex II are nuclear-encoded. A point mutation in mev-1, the gene encoding the SDHC-1 subunit of Complex II, increases ROS production and decreases lifespan, while loss-of-function is lethal. These phenotypes have been recapitulated in an orthologous mouse model, suggesting an evolutionarily conserved role for complex II. Here, we developed an optogenetic tool to study mitochondrial respiratory chain function and determine how complex II contributes to systems physiology. We expressed the genetically-encoded 'singlet oxygen generator' miniSOG as a Pmev-1::MEV-1::miniSOG::mev-1 (3' UTR) fusion in trans to the endogenous mev-1 gene as single-copy MosSCI insertion. We then used this strain to conduct Chromophore-Assisted Light Inactivation (CALI) of complex II activity. In response to blue light, miniSOG produces ROS that are highly reactive and act locally, allowing for the selective inactivation of a target protein. The mev-1::miniSOG transgene complemented a lethal mev-1(tm1081) deletion, suggesting that it was active and targeted to the mitochondrial inner membrane. We isolated mitochondria from the transgenic strain and found a photo-titratable loss of complex II activity with no effect on mitochondrial citrate synthase (Krebs cycle) or complex IV (respiratory chain) activities. Using this transgenic model we determined the effects of in-vivo acute complex II inactivation on physiologic outputs including development, brood size, stress resistance, activation of stress resistance pathways, and lifespan. Collectively, our results show that complex II activity is important under conditions of high energy demand or stress. This optogenetic approach provides spatial and temporal control over mitochondrial function and represents a new model to interrogate the role of complex II activity in mitochondrial metabolism.

Lim, Yunki et al. (2019) International Worm Meeting "Fndc-1 is ubiquitin-independent mitophagy receptor involved in paternal mitochondria elimination in C. elegans."

Galy, Vincent, Rubio, Karinna, Nehrke, Keith, Brookes, Paul S., Lim, Yunki, Molina, Paola A.

[International Worm Meeting, 2019]

Mitochondria are inherited through the maternal germline, and while paternal mitochondria elimination (PME) occurs following fertilization through autophagy, the mechanism(s) that assure paternal selectivity are not well understood. FUNDC1 (FUN14 domain containing1) is a mitochondrial outer-membrane protein that contributes to damaged mitochondria degradation following ischemia/reperfusion injury in mammalian cells. FNDC-1, the C. elegans ortholog of FUNDC1, is widely expressed in worm somatic tissues and mediates hypoxic mitophagy. Here, we report that FNDC-1 is not expressed in oocytes but strongly expressed in sperm, where it co-localizes with a mitochondria membrane marker. Loss of fndc-1 retards the rate of both PME and paternal mitochondrial DNA degradation following fertilization. This effect is specific to the paternal germline, as maternal fndc-1(lf) does not affect PME. In addition, the degradation of membranous organelles, a nematode-specific membrane compartment contributed by sperm that is also degraded through autophagy, is unaffected by fndc-1(lf) in either maternal or paternal germlines, consistent with FNDC-1 being specific to paternal mitophagy and not general autophagy. Finally, fndc-1(lf) does not impact the recruitment of LC3 homologs, LGG-1 and LGG-2, to mitochondria. Collectively, these findings represent the first report of a ubiquitin-independent mitophagy receptor playing a role in the selective elimination of paternal mitochondria.

Lim, Yunki et al. (2019) International Worm Meeting "The mitophagy receptor FUNDC1 contributes to hypoxia-reoxygenation injury in C. elegans."

Park, Eun Chan, Berry, Brandon, Wojtovich, Andrew, Rongo, Christopher, Nehrke, Keith, Brookes, Paul S., Lim, Yunki

[International Worm Meeting, 2019]

Mitochondria are the metabolic hub of the cell and have a nearly pervasive impact on pathophysiology. Hence, the molecular components and signaling pathways that comprise mitochondrial quality control are tightly regulated and critical for normal stress responses. Among these are pathways for sensing mitochondrial proteostasis such as the mitochondrial unfolded protein response (UPRmt) and for recycling damaged mitochondria such as mitophagy. FUNDC1 (FUN14 domain containing 1) is a mitochondrial outer membrane protein and a hypoxia-induced mitophagy receptor that regulates hypoxic cell death in mammals. Here, using mito-mKeima (pH-dependent dual excitation fluorophore protein) to monitor mitophagy, we show that T06D8.7/fndc-1 encodes the C. elegans FUNDC1 ortholog and is required to protect nematodes from hypoxia-reoxygenation (H/R) injury. Consistent with previous results demonstrating protection from H/R injury by activation of the UPRmt, loss of the central UPRmt transcription factor atfs-1 suppresses H/R protection. However, canonical UPRmt reporter genes were not activated in the fndc-1(lf) mutant, suggesting that protection was seen in fndc-1(lf) worms may occur through a novel or restricted arm of the UPRmt pathway. Mechanistically, mitochondrial respiration was not impacted by the loss of fndc-1; instead, increased ATP levels and changes in the expression of genes that regulate glycolysis underlie metabolic rewiring in the mutant. Since these changes also depend upon atfs-1, our results highlight a connection between FNDC-1-mediated mitophagy and a restricted branch of the UPRmt that impacts metabolism and subsequent susceptibility to H/R injury.

Paul Sternberg (2002) Worm Breeder's Gazette "Position at Caltech, CA"

Paul Sternberg

[Worm Breeder's Gazette, 2002]

CURATOR. Will annotate gene functions in C. elegans , using Gene Ontology (Nature Genetics [2000], vol. 25, pp. 25-29). Duties include: analysing gene functions in the primary literature; judging the optimal description of these functions in Gene Ontology, inventing new terms for Gene Ontology where necessary; and incorporating these descriptions into Wormbase. A Ph.D. in some area of biology and substantial C. elegans experience are required. The successful job candidate will have broad scientific erudition, verbal articulacy, and creative intelligence as well as patience and a willingness to work hard. Computer literacy in UNIX or Linux is a plus, but is not required. Direct inquiries to Paul Sternberg (pws@its.caltech.edu).