Depletion of the Central Metabolite NAD Leads to Oncosis-mediated Cell Death

Nagro, Christopher Del; Xiao, Yang; Rangell, Linda; Reichelt, Mike; O’Brien, Tom

doi:10.1074/jbc.m114.580159

Cited by 63 publications

(64 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because ATP levels are still maintained (∼75% of uninjured axons), delaying NAD + loss is sufficient to maintain ATP levels for a prolonged period, and thus extend axon health. Such findings are consistent with other reports suggesting that NAD + must be depleted below 5% to impact cell viability (29). These observations collectively demonstrate that SARM1 (K597E) impairs injury-induced activation of the SARM1 protein and reveal a surprising link between autoinhibition and N-terminal and SARM1 TIR domains.…”

Section: Mutant Sarm1 (K597e) Acts As a Dominant Negative And Blockssupporting

confidence: 81%

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

125

View full text Add to dashboard Cite

Axon injury in response to trauma or disease stimulates a selfdestruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD + and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD + loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD + loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD + loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.A xon degeneration in response to injury or disease is a hallmark of neurological disorders of the peripheral and central nervous systems. Akin to programmed cell death pathways, such as apoptosis, axon injury in response to disease or trauma stimulates a local signaling cascade that executes destruction of the injured axon segment (1). Despite growing attention, the molecular details of this prodegenerative cascade are still unclear. A more substantial understanding of the molecular factors that participate in this axon destructive process will likely provide new therapeutic strategies for peripheral neuropathies and other neurodegenerative conditions.Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2, 3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4). Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5, 6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen gluc...

show abstract

Section: Mutant Sarm1 (K597e) Acts As a Dominant Negative And Blockssupporting

confidence: 81%

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

125

View full text Add to dashboard Cite

show abstract

“…None of these events seem to be involved in BL plus APO866-induced cell death. Del Nagro and co-workers recently demonstrated that oncosis is the predominant form of cell death induced by NAMPT inhibitor, especially in treated-cancer cells that do not activate caspases [20] but this type of cell death was not addressed in the present study.…”

Section: Discussionmentioning

confidence: 64%

Combinative effects of β-Lapachone and APO866 on pancreatic cancer cell death through reactive oxygen species production and PARP-1 activation

et al. 2015

View full text Add to dashboard Cite

“…There is limited information on molecular mechanisms underlying the crosstalk between specific types of cancer cell death. A recent study (Del Nagro et al 2014) demonstrated that cancer cell lines with a slower rate of ATP depletion (average t 1 ⁄ 2 of 45 h) activate caspase-3 and show evidence of apoptosis and autophagy, whereas cell lines with rapid depletion of ATP (average t 1 ⁄ 2 of 32 h) do not activate caspase-3 or show signs of apoptosis or autophagy. Oncosis was identified as a predominant form of cell death once the ATP level was depleted by O20-fold.…”

Section: Discussionmentioning

confidence: 99%

Glucose-deprivation increases thyroid cancer cells sensitivity to metformin

Bikas¹,

Jensen²,

Patel³

et al. 2015

Endocrine-Related Cancer

View full text Add to dashboard Cite

Metformin inhibits thyroid cancer cell growth. We sought to determine if variable glucose concentrations in medium alter the anti-cancer efficacy of metformin. Thyroid cancer cells (FTC133 and BCPAP) were cultured in high-glucose (20 mM) and low-glucose (5 mM) medium before treatment with metformin. Cell viability and apoptosis assays were performed. Expression of glycolytic genes was examined by real-time PCR, western blot, and immunostaining. Metformin inhibited cellular proliferation in high-glucose medium and induced cell death in low-glucose medium. In low-, but not in high-glucose medium, metformin induced endoplasmic reticulum stress, autophagy, and oncosis. At micromolar concentrations, metformin induced phosphorylation of AMP-activated protein kinase and blocked p-pS6 in low-glucose medium. Metformin increased the rate of glucose consumption from the medium and prompted medium acidification. Medium supplementation with glucose reversed metformin-inducible morphological changes. Treatment with an inhibitor of glycolysis (2-deoxy-D-glucose (2-DG)) increased thyroid cancer cell sensitivity to metformin. The combination of 2-DG with metformin led to cell death. Thyroid cancer cell lines were characterized by over-expression of glycolytic genes, and metformin decreased the protein level of pyruvate kinase muscle 2 (PKM2). PKM2 expression was detected in recurrent thyroid cancer tissue samples.In conclusion, we have demonstrated that the glucose concentration in the cellular milieu is a factor modulating metformin's anti-cancer activity. These data suggest that the combination of metformin with inhibitors of glycolysis could represent a new strategy for the treatment of thyroid cancer.

show abstract

Depletion of the Central Metabolite NAD Leads to Oncosis-mediated Cell Death

Cited by 63 publications

References 44 publications

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Combinative effects of β-Lapachone and APO866 on pancreatic cancer cell death through reactive oxygen species production and PARP-1 activation

Glucose-deprivation increases thyroid cancer cells sensitivity to metformin

Contact Info

Product

Resources

About

Depletion of the Central Metabolite NAD Leads to Oncosis-mediated Cell Death

Cited by 63 publications

References 44 publications

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

Combinative effects of β-Lapachone and APO866 on pancreatic cancer cell death through reactive oxygen species production and PARP-1 activation

Glucose-deprivation increases thyroid cancer cells sensitivity to metformin

Contact Info

Product

Resources

About

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation