Liu S et al. (2013) Chemosphere "The non-target organism Caenorhabditis elegans withstands the impact of sulfamethoxazole."

Steinberg CE, Pan B, Saul N, Liu S, Menzel R

[Chemosphere, 2013]

The widespread usage of antibiotics in agriculture leads to releases into the environment, but there is insufficient knowledge of the side-effects on non-target organisms. Therefore, we investigated the effects of the sulfonamide-antibiotic sulfamethoxazole (SMX) on Caenorhabditis elegans at phenotypic, biochemical and molecular biological levels. Multiple endpoints, including life history traits, thermal stress resistance and lipid peroxidation, as well as gene expression profiles, were determined after exposure of the nematodes to SMX. In contrast to expectations, SMX prolonged the lifespan and increased both the body size and pharynx pumping rate. On the other hand, SMX delayed reproductive timing and caused lipid peroxidation. The total number of offspring and thermal stress resistance were unaffected. The up-regulation of hsp-16.1 indicated stress in general and the increased lipid peroxidation oxidative stress in particular. This oxidative stress indicated that mitohormesis was the likely cause of the longevity and that enhanced pumping frequency was probably the reason for the increased growth. The sole adverse effect was delayed initial reproduction. This delay, however, can be crucial for r-strategists, such as the bacterivorous model animal used, in sustaining their populations in the environment in the presence of predators. Bacterivorous animals, in turn, are essential to maintaining nutrient recycling via the microbial loop.

Liu S et al. (2021) FEBS J "Multifaceted Roles of Mitochondrial Stress Responses under ETC Dysfunction - Repair, Destruction and Pathogenesis."

Liu S, Jiang H

[FEBS J, 2021]

Electron transport chain (ETC) dysfunction is a common feature of mitochondrial diseases and induces severe cellular stresses, including mitochondrial membrane potential (_m ) reduction, mitochondrial matrix acidification, metabolic derangements and proteostatic stresses. Extensive studies of ETC dysfunction in yeast, C. elegans, cultured cells and mouse models have revealed multiple mitochondrial stress response pathways. Here, we summarize the current understanding of the triggers, sensors, signaling mechanisms, and the functional outcomes of mitochondrial stress responses in different species. We highlight _m reduction as a major trigger of stress responses in different species, but the responses are species-specific and the outcomes are context-dependent. ETC dysfunction elicits a mitochondrial unfolded protein response (UPR^mt ) to repair damaged mitochondria in C. elegans, and activates a global adaptive program to maintain _m in yeast. Yeast and C. elegans responses are remarkably similar at the downstream responses, although they are activated by different signaling mechanisms. UPR^mt generally protects ETC-defective worms, but its constitutive activation is toxic for wildtype worms and worms carrying mutant mtDNA. In contrast to lower organisms, ETC dysfunction in mammals mainly activates a mitochondrial integrated stress response (ISR^mt ) to reprogram metabolism and a PINK1-Parkin mitophagy pathway to degrade damaged mitochondria. Accumulating in vivo results suggest that the ATF4 branch of ISR^mt exacerbates metabolic derangements to accelerate mitochondrial disease progression. The in vivo roles of mitophagy in mitochondrial diseases are also context-dependent. These results thus reveal the common and unique aspects of mitochondrial stress responses in different species and highlight their multifaceted roles in mitochondrial diseases.

Liu, S. et al. (2009) International Worm Meeting "CNG channels and TRPV channel proteins are involved in the thermal avoidance response in Caenorhabditis elegans."

Liu, S., Baumeister, R.

[International Worm Meeting, 2009]

Upon exposure to noxious temperature, Caenorhabditis elegans executes an escape reflex (Tav response) similar to the response to body touch. We had previously shown that sensory neurons in the head and tail, but not in the midbody region, are involved in the perception of heat (Wittenburg 1999 PNAS). For finding candidate sensory neurons acting as thermonociceptors, we developed a modified neuron ablation method using a 2-photon laser. For this purpose, we labeled individual sets of neurons with GFP for ablation, and identified two pairs of head sensory neurons and one pair of tail sensory neurons as thermonociceptors. In order to characterize the moleculars of the thermal avoidance response in these sensory cells at the molecular level, we focused on a functional assessment of channel proteins that are candidates for heat receptors involved in the Tav behavior. In vertebrates, the capsaicin-sensitive vanilloid receptor VR1, a channel protein of the TRP family, has been shown to be involved in the perception of heat, capsaicin, and low pH. Our data indicate that the double mutants of the two VR1 homologous in C. elegans ocr-2(vs29)osm-9(ky10) have reduced TAV response from 95.1% to 73.5% in the head and from 68.1% to 14.5% in the tail. The results suggest that OSM-9 and OCR-2 are required, but are not sufficient, for the perception of noxious heat and that these two VR1 channels have conserved functions across different species. In vertebrates, the cyclic nucleotide-gated channels play a significant role in sensory neurons in visual and olfactory systems. Indeed, the mutants of the two homologous cGMP-gated channels subunits, tax-2(p671) and tax-4(p678), display reduced head Tav response (95.1% to 70.7% and 68.8%, respectively). These defects can be rescued by transgenic expression of the tax-2 or tax-4 cDNA in only two head thermonociceptors we had identified in this study. This indicates that TAX-2 and TAX-4 are required cell autonomously for thermonociception in at least two pair of sensory cells. All together, our data suggest that thermal avoidance response in C. elegans is mediated by a cGMP signaling pathway that includes the cGMP-gated heteromeric channel TAX-2/TAX-4 and also require the TRPV channel proteins.

Liu S et al. (2021) Cell Metab "Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD+ to alleviate mitochondrial disease."

Dong M, Liu S, Li N, Yang J, Ma Y, Li X, Fu S, Liu Q, Wang G, Cao Y, Jiang H, Li L, Shan Y

[Cell Metab, 2021]

Electron transport chain (ETC) dysfunction or hypoxia causes toxic NADH accumulation. How cells regenerate NAD⁺ under such conditions remains elusive. Here, integrating bioinformatic analysis and experimental validation, we identify glycerol-3-phosphate (Gro3P) biosynthesis as an endogenous NAD⁺-regeneration pathway. Under genetic or pharmacological ETC inhibition, disrupting Gro3P synthesis inhibits yeast proliferation, shortens lifespan of C.elegans, impairs growth of cancer cells in culture and in xenografts, and causes metabolic derangements in mouse liver. Moreover, the Gro3P shuttle selectively regenerates cytosolic NAD⁺ under mitochondrial complex I inhibition; enhancing Gro3P synthesis promotes shuttle activity to restore proliferation of complex I-impaired cells. Mouse brain has much lower levels of Gro3P synthesis enzymes as compared with other organs. Strikingly, enhancing Gro3P synthesis suppresses neuroinflammation and extends lifespan in the Ndufs4^-/- mice. Collectively, our results reveal Gro3P biosynthesis as an evolutionarily conserved coordinator of NADH/NAD⁺ redox homeostasis and present a therapeutic target for mitochondrial complex I diseases.

Liu S et al. (2012) PLoS One "Temperature- and touch-sensitive neurons couple CNG and TRPV channel activities to control heat avoidance in Caenorhabditis elegans."

Schulze E, Liu S, Baumeister R

[PLoS One, 2012]

BACKGROUND: Any organism depends on its ability to sense temperature and avoid noxious heat. The nematode Caenorhabditis elegans responds to noxious temperatures exceeding 35C and also senses changes in its environmental temperature in the range between 15 and 25C. The neural circuits and molecular mechanisms involved in thermotaxis have been successfully studied, whereas details of the thermal avoidance behavior remain elusive. In this work, we investigate neurological and molecular aspects of thermonociception using genetic, cell biological and physiological approaches. METHODOLOGY/PRINCIPAL FINDINGS: We show here that the thermosensory neurons AFD, in addition to sensing temperature within the range within which the animals can thrive, also contribute to the sensation of noxious temperatures resulting in a reflex-like escape reaction. Distinct sets of interneurons are involved in transmitting thermonociception and thermotaxis, respectively. Loss of AFD is partially compensated by the activity of a pair of multidendritic, polymodal neurons, FLP, whereas laser ablation of both types of neurons abrogated the heat response in the head of the animals almost completely. A third pair of heat sensory neurons, PHC, is situated in the tail. We find that the thermal avoidance response requires the cell autonomous function of cGMP dependent Cyclic Nucleotide-Gated (CNG) channels in AFD, and the heat- and capsaicin-sensitive Transient Receptor Potential Vanilloid (TRPV) channels in the FLP and PHC sensory neurons. CONCLUSIONS/SIGNIFICANCE: Our results identify distinct thermal responses mediated by a single neuron, but also show that parallel nociceptor circuits and molecules may be used as back-up strategies to guarantee fast and efficient responses to potentially detrimental stimuli.

(2015) Science "Erratum for the Report "Recruitment of RNA polymerase II by the pioneer transcription factor PHA-4" by H.-T. Hsu, H.-M. Chen, Z. Yang, J. Wang, N. K. Lee, A. Burger, K. Zaret, T. Liu, E. Levine, S. E. Mango."

[Science, 2015]

Kaplan HS et al. (2018) Neuron "Sensorimotor Integration for Decision Making: How the Worm Steers."

Zimmer M, Kaplan HS

[Neuron, 2018]

Animals' movements actively shape their perception and subsequent decision making. In this issue of Neuron, Liu etal. (2018) show how C.elegans nematodes steer toward an odorant: a dedicated interneuron class integrates oscillatory olfactory signals, generated by head swings, with corollary discharge motor signals.

Ali L et al. (2020) J Cell Biol "Mitochondrial translation, dynamics, and lysosomes combine to extend lifespan."

Ali L, Haynes CM

[J Cell Biol, 2020]

In this issue, Liu et al. (2019. J. Cell. Biol.https://doi.org/10.1083/jcb.201907067) find that the inhibition of mitochondrial ribosomes in combination with impaired mitochondrial fission or fusion increases C. elegans lifespan by activating the transcription factor HLH-30, which promotes lysosomal biogenesis.

Vinci CR et al. (2007) J Biol Chem "Recognition of age-damaged (R,S)-adenosyl-L-methionine by two methyltransferases in the yeast Saccharomyces cerevisiae."

Vinci CR, Clarke SG

[J Biol Chem, 2007]

The biological methyl donor, S adenosylmethionine (AdoMet), can exist in two diastereoisomeric states with respect to its sulfonium ion. The "S" configuration, (S,S)AdoMet, is the only form that is produced enzymatically as well as the only form used in almost all biological methylation reactions. Under physiological conditions, however, the sulfonium ion can spontaneously racemize to the "R" form, producing (R,S)AdoMet. As of yet, (R,S)AdoMet has no known physiological function and may inhibit cellular reactions. In this study, two enzymes have been found in Saccharomyces cerevisiae that are capable of recognizing (R,S)AdoMet and using it to methylate homocysteine to form methionine. These enzymes are the products of the SAM4 and MHT1 genes, previously identified as homocysteine methyltransferases dependent upon AdoMet and S-methylmethionine respectively. We find here that Sam4 recognizes both (S,S) and (R,S)AdoMet, but its activity is much higher with the R,S form. Mht1 reacts with only the R,S form of AdoMet while no activity is seen with the S,S form. R,S-specific homocysteine methyltransferase activity is also shown here to occur in extracts of Arabidopsis thaliana, Drosophila melanogaster, and Caenorhabditis elegans, but has not been detected in several tissue extracts of Mus musculus. Such activity may function to prevent the accumulation of (R,S)AdoMet in these organisms.

(2019) Proc Natl Acad Sci U S A "Correction for Liu et al., Reciprocal modulation of 5-HT and octopamine regulates pumping via feedforward and feedback circuits in C. elegans."

[Proc Natl Acad Sci U S A, 2019]