To regenerate efficiently, a damaged neuron must undergo molecular and metabolic rearrangement to induce and endure a range of complex cellular processes (Mahar and Cavalli, 2018; Taub et al., 2018; Yang et al., 2020). These processes are extremely metabolically challenging, energy demanding, and critical for the regenerative capacity of a neuron (Byrne et al., 2014; Cartoni et al., 2016; He and Jin, 2016; Yang et al., 2020). The importance of metabolic pathways, particularly in neuronal regeneration including the insulin-signaling pathway, energy metabolism, and mitochondrial function have been reported in research articles by several groups (Byrne et al., 2014; Cartoni et al., 2016; Han et al., 2016; Han et al., 2020). Nonetheless, critical questions remain as to the alterations in cellular metabolism and metabolic pathways linked with energy production in a damaged and regenerating neurons and how these processes might be exploited for therapeutic benefits.

In a previous study our group demonstrated that perturbation in O-GlcNAc signaling, a post-translational modification of serine and threonine that is known to act as a nutrient sensor, substantially increased axonal regeneration in Caenorhabditis elegans (C. elegans) (Taub et al., 2018). Carrying out in vivo laser axotomies, we demonstrated that a reduction of O-GlcNAc levels, due to deletion mutation of the ogt-1, induces the AKT-1 branch of the insulin-signaling pathway to utilize glycolysis and significantly enhanced neuronal regeneration. Inhibition of the glycolytic pathway through RNAi knockdown of phosphoglycerate kinase (pgk-1) or loss of function of phosphofructokinase-1.1 (pfk-1.1) specifically suppressed ogt-1 enhanced regeneration but did not alter wild-type regeneration (Taub et al., 2018). Furthermore, supplementation with glucose in wild-type animals is sufficient to increase axonal regeneration after axotomy (Taub et al., 2018). These observations established the significance of glycolytic metabolism to control and enhance neuronal regeneration.

To date key questions remain as to what specific metabolic pathways are stimulated in the ogt-1 mutant background and what cellular processes are augmented to increase regenerative capacity. Numerous reports suggest that increased glycolysis averts metabolic flux toward OCMto regulate numerous biological processes including molecular reprogramming, immunological functions as well as neuronal development and function (Iskandar et al., 2010; Konno et al., 2017; Yu et al., 2019b). In addition, studies have reported the importance of metabolic amendments of OCM, the SSP and the TSP in neuronal development, structure, function, and regeneration (Iskandar et al., 2010; Bonvento and Bolaños, 2021; Lam et al., 2021; Chen et al., 2022). Measuring neuronal regeneration in C. elegans following laser axotomy under genetic and pharmacological perturbations of metabolic pathways, we demonstrate that both functional OCM and glycolytic flux towards OCM via the SSP are essential for enhanced regeneration in ogt-1 animals. From there, we observed that metabolic pathways from OCM through the TSP, that result in cystathionine metabolism into Acetyl-CoA via the vitamin B12 independent shunt pathway, is also critical. Taken together our results illustrate how ogt-1 acts as a major regulator of metabolic pathways to orchestrate and maximize the regenerative response in a damaged neuron and suggest that OCM and its related pathways could serve as a potent neurotherapeutic target.

In order to initiate and sustain the energetically demanding growth state required for effective regeneration there must be sufficient modulation of the underlying molecular and metabolic processes within the damaged neuron (He and Jin, 2016). Numerous studies have focused on the molecular and genetic mechanisms involved in axonal regeneration (Sun et al., 2014; Chisholm et al., 2016; Chung et al., 2016). Yet the role of metabolic pathways is relatively less explored, despite its clear role in determining regenerative capacity (Taub et al., 2018; Li et al., 2020; Yang et al., 2020). Previously, our group demonstrated that genetically altered O-GlcNAc levels can substantially enhance neuronal regeneration through modulation of the neuronal metabolic response (Taub et al., 2018). Exploiting the genetic and optical accessibility of C. elegans, we demonstrated that a reduction of O-GlcNAc levels (via ogt-1 deletion mutation), a proxy for the metabolic deficit, supports increased regenerative capacity (Taub et al., 2018). In this study, we verified these effects in the ogt-1(deletion) mutation as before (Figure 1B) and found similar results in the catalytically dead mutant allele (OG1135) (Figure 1B), demonstrating that the lack of OGT-1 enzymatic activity is important as opposed to a possible non-catalytic function (Konzman et al., 2022; Pravata et al., 2019). Earlier, we found that disruption of key elements of the glycolytic pathway selectively eliminates the enhanced regeneration of the ogt-1 mutant (Taub et al., 2018). Glycolysis is a key energy source for neurons, particularly under energy-limiting conditions (Jang et al., 2016) and in developing neurons that foster high axonal growth rates (Han et al., 2016; Zheng et al., 2016; Han et al., 2020). We further verified this by neuron-specific RNAi knockdown of atp-3, which significantly reduces cellular ATP levels (Soto et al., 2020) and blocks the enhance regeneration in ogt-1 animals (Figure 1D). While our previous work established that the early steps of neuronal glycolysis are a key component of enhanced axonal regeneration following injury in ogt-1 worms (Taub et al., 2018), key questions remained as to the specific metabolic pathways that are amended and involved to support regeneration.

Our results here indicate that a complex metabolic pathway beyond that of canonical glycolysis is involved (Figure 5). In our earlier study, we demonstrated the importance of early glycolytic enzymes (pfk-1.1 and pgk-3) in the ogt-1 effect (Taub et al., 2018). However, we found here that this does not extend to the complete glycolytic pathway as neuron-specific disruption of pyruvate kinase (pyk-1), which catalyzes the final step of glycolysis to produce pyruvate, had no effect on regeneration in ogt-1 (Figure 1D). This is in accordance with the reported effects of O-GlcNAcylation on these enzymes. High O-GlcNAcylation decreases pfk-1.1 function (Bacigalupa et al., 2018). Despite the fact that high O-GlcNAcylation also destabilizes the pyruvate kinase, PKM1/2, complex (Wang et al., 2017), reports show that inhibition of ogt-1 results in low pyruvate kinase expression and cellular activity (Yu et al., 2019a). The ogt-1 mutation, which reduces O-GlcNAcylation, is therefore expected to increase pfk-1.1, and reduce pyk-1, activity, respectively, which agrees with their measured importance in ogt-1 neuron regeneration.

Figure 5

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As these results indicate that the increased regeneration in ogt-1 mutants does not entail direct ATP production in the TCA cycle of canonical glycolysis, we further adopted an unbiased approach performing genome-wide gene expression analysis to identify additional pathways involved. Through GO and KEGG pathway classification analysis of RNA-seq data from wild-type and ogt-1 mutant animals, we identified several metabolic pathways altered in both whole animals and FACs sorted neuron samples (Figure 2B–E, Figure 2—source data 1, and Figure 2—figure supplement 2C–D, Figure 2—source data 2). In addition to numerous genes and cellular processes with known roles in regeneration such as amino acid, nucleotide metabolism, lipid synthesis, methylation, and glycolysis (Ducker and Rabinowitz, 2017; Clare et al., 2019), our analysis further identified metabolic processes including glutathione and s-adenosyl methionine (SAM) metabolism, energy metabolism, and ATP synthesis that were significantly enriched in the ogt-1 background. This pathway enrichment analysis indicates the involvement of OCM and its associated pathways in enhanced regeneration in ogt-1 animals (Figure 2B–F and Figure 2—figure supplement 2A–B). These results were further confirmed via specific gene expression analysis using qRT-PCR (Figure 2G and Figure 4D) and indicate the importance of OCM and the TSP as key metabolic pathways altered by the ogt-1 mutation (Figure 2D–F).

OCM is involved in a wide array of cellular processes including nucleotide biosynthesis (purines and thymidine), amino acid homeostasis (glycine, serine, and methionine), epigenetic maintenance (nucleic acid and histone methylation), and redox defense (Ducker and Rabinowitz, 2017). Enhanced glycolysis drives OCM through the SSP (Locasale, 2013; Yu et al., 2019b) that is known to be involved in several neuronal conditions including, neuronal growth, neural tube defect, and Alzheimer’s disease (Coppede, 2010; Bonvento and Bolaños, 2021; Lionaki et al., 2022). Through a combination of genetic manipulation, pharmacological treatment, and metabolic supplementation in our C. elegans neuronal regeneration assays, we have determined the specific metabolic pathway by which OCM contributes to the enhanced regeneration in the ogt-1 mutant. The complete pathway is illustrated in green in Figure 5. We found that metabolic flux diverted from the early steps of glycolysis towards OCM through SSP is crucial, which is in agreement with earlier reports where enhanced glycolysis diverts metabolic flux towards OCM through SSP (Yu et al., 2019b). This was most dramatically illustrated by the reduction in regeneration from pharmacological, or genetic, disruption of phgdh-1 (C31C9.2, ortholog of human PHGDH), a key element of the SSP. The role of the SSP was further confirm by serine supplementation in the akt-1 and ogt-1 double mutant (ogt-1;akt-1), which restored the enhanced ogt-1 regeneration blocked by the akt-1 mutation (Figure 3—figure supplement 1A). These results are in agreement with earlier metabolomic findings that enhanced glycolysis (Yu et al., 2019b) and/or knock down of PMK1/2 (mammalian ortholog of pyk-1) diverts metabolic flux toward serine synthesis pathway to sustain cellular metabolic requirements (Yu et al., 2019a). Here, we have focused our study on SSP, OCM, and TSP because the pathway analysis of our RNA-seq data suggested they were most affected in ogt-1 animals. However, it is likely that additional metabolic pathways associated with glycolysis, such as the pentose phosphate pathway (PPP, elements of which are dynamically O-GlcNAcylated in response to hypoxic stress Rao et al., 2015), are also affected by ogt-1 mutation and pyk-1 knock down. Further investigation of these additional pathways should prove beneficial in the future.

Although OCM is involved in both lipogenesis and DNA transmethylation (Kersten, 2001; Yu et al., 2019b) that could potentially play significant roles in increasing neuron regeneration (Iskandar et al., 2010), we found that the regeneration effects of ogt-1 were primarily dependent on L-cystathionine metabolism via the downstream TSP (Figure 4C). The TSP is influenced by OCM and its metabolites and has been reported to play an important role in neurodegenerative diseases and ATP production (Giese et al., 2020; Lam et al., 2021). We found that cystathionine supplementation rescued the prohibitory effects of blocking the SSP pathway in the ogt-1 background (Figure 4C). Testing branches of the TSP, we found that only the vitamin B12 independent shunt pathway was required, via Acyl CoA dehydrogenase (acdh-1), for ogt-1-mediated enhanced regeneration. The shunt pathway generates Acetyl-CoA that will drive ATP production through the Kreb’s cycle ultimately bringing the metabolic consequences of ogt-1 back to cellular energy production and utilization as we demonstrated in Taub et al., Though, we observed a significant decrease in ATP levels (Figure 1F, Figure 1—figure supplement 1C) and no difference in ATP utilization (Figure 1—figure supplement 1D) in ogt-1 animals, these observations were either in whole worms or in nonneuronal tissues rather than neuron-specific. Indeed, the down regulation of pyk-1 from ogt-1 inhibition has been associated with total reduced ATP levels previously (Dey et al., 2019). Regardless, our work here has now deciphered a specific metabolic pathway through which the enhanced regenerative effect of ogt-1 occurs.

While the ogt-1 mutant rewires metabolic flux through a specific pathway to support and sustain enhance regeneration, we also discovered several additional conditions where restriction or diversion of metabolic flux in wild-type animals has similar beneficial effects. For instance, the HBS pathway nominally shunts off ~5% of glycolytic flux (Marshall et al., 1991; Bond and Hanover, 2015). We found that blocking the HBS pathway through RNAi against gfat-1 and gfat-2 (Yi et al., 2012; Jóźwiak and Forma, 2014; Kim et al., 2018), appears to divert metabolic flux towards glycolysis and results in enhanced regeneration in WT animals similar to that of ogt-1 (Figure 1C). Likewise, pyk-1 knockdown increases regeneration in WT and is known to divert metabolic flux toward the SSP (Yu et al., 2019a). Within OCM, we found that transmethylation pathways required for epigenetic modifications and phospholipid synthesis were not essential for the enhanced regeneration in ogt-1 animals but that blocking histone methyl transferases in WT animals increased regeneration (Figure 3I). In addition, supplementation in wild type with the metabolite, L-methionine (product of metr-1), which increases OCM, phenocopied the enhance regeneration of the ogt-1 mutant (Figure 3F) as did blocking neuronal glutathione synthesis within the TSP (gss-1 RNAi) (Figure 4B). While in the above instances restriction or enhancement of specific metabolic steps could be augmenting the same pathway utilized in ogt-1 regeneration, in other cases clearly alternative pathways are at work. For example, pharmacologically (NCT502 treatment) or genetically (phgdh-1 knock down) blocking SSP which restricts the ogt-1 regeneration pathway effectively increases regeneration in WT. This effect is possibly due to increased metabolic flux through glycolysis, as we observed increased activity of pyk-1 after NCT502 treatment (Figure 3—figure supplement 1C). Likewise, we had previously found that mutation of the O-GlcNAcase, oga-1, which increases O-GlcNAc levels, also increased neuron regeneration in C. elegans, but did so through an independent pathway of enhanced mitochondrial stress response (Taub et al., 2018).

Thus, within the complex web of cellular metabolism and energy production there appears to be numerous pathways for metabolite utilization that are beneficial for neuron regeneration. Here, employing genetic tools, we have defined a specific array of metabolic pathways (glycolysis, SSP, OCM, and TSP) through which the ogt-1 mutation diverts metabolic flux to increase neuronal regeneration. It is important to emphasize the accessibility of these metabolic effects to pharmacological treatment and/or metabolite supplements. For example, we previously demonstrated increased regeneration in wild-type animals with glucose supplementation (Taub et al., 2018). Here, we find similar effects with L-methionine supplementation or treatment with the SSP blocking agent NCT502 in wild-type animals. Nutrient supplements and metabolic drug targets have been employed in neurotherapeutic treatments and prevention in numerous contexts including neuronal developmental defects (Greene et al., 2017; Businaro et al., 2021; Wu et al., 2022) and age-associated neurodegenerative diseases (Stempler et al., 2014; Businaro et al., 2021). While our current study has specifically focused on the neuronal regeneration of the mechanosensory neurons in C. elegans, O-GlcNAc signaling has been widely implicated in regulating various neuronal cellular processes in higher organisms. This includes axon growth, synaptic plasticity, and neurite outgrowth (Tian et al., 2023; Mutalik and Gupton, 2021) and has been linked to the modulation of gene expression during neuronal repair in higher animals including mammals (Lee et al., 2021; Su and Schwarz, 2017). These studies suggest that functions of O-GlcNAc signaling are conserved throughout the nervous system and across species. Future work will be required to determine to what degree this holds true specifically in the context of neuronal regeneration. Regardless, our work here demonstrates the role of OCM, SSP, and TSP metabolic pathways in the increased regenerative capacity of a damaged neuron in ogt-1 C. elegans and highlights the potential power for such metabolic targets in the treatment of neuronal injury.

Key resource table: List of E. coli and C. elegans strains, Chemicals, Drugs, Kits, and RT-PCR primers used in this study.

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Author details

1. Dilip Kumar Yadav

   Department of Pharmacology, Physiology and Biophysics, Chobanian & Avedisian School of Medicine, Boston University, Boston, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing, Conceived and designed experiments. Performed all the experiments and aided in the analysis of data

   For correspondence

   dyadav1@bu.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0232-7387

2. Andrew C Chang

   Department of Pharmacology, Physiology and Biophysics, Chobanian & Avedisian School of Medicine, Boston University, Boston, United States

   Contribution

   Data curation, Investigation, Aided in confocal imaging and analysis

   Competing interests

   No competing interests declared

3. Noa WF Grooms

   Department of Bioengineering, Northeastern University, Boston, United States

   Contribution

   Investigation, Aided in laser ablation experiments

   Competing interests

   No competing interests declared

4. Samuel H Chung

   Department of Bioengineering, Northeastern University, Boston, United States

   Contribution

   Funding acquisition, Investigation, Project administration, Provided laser ablation equipment and guidance

   Competing interests

   No competing interests declared

5. Christopher V Gabel

   1. Department of Pharmacology, Physiology and Biophysics, Chobanian & Avedisian School of Medicine, Boston University, Boston, United States
   2. Neurophotonics Center, Boston University, Boston, United States

   Contribution

   Conceptualization, Funding acquisition, Investigation, Writing – original draft, Project administration, Writing – review and editing, Conceived and designed experiments. Aided in all experiments and analysis of data

   For correspondence

   cvgabel@bu.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2763-3938

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