c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration
Open accessAbstract
Mitochondrial dysfunction is a key pathological feature of many different types of neurodegenerative disease. Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) has been attracting much attention as an important molecule for inducing axonal degeneration and neuronal cell death by causing loss of NAD (NADH). However, it has remained unclear what exactly regulates the SARM1 activity. Here, we report that NAD + cleavage activity of SARM1 is regulated by its own phosphorylation at serine 548. The phosphorylation of SARM1 was mediated by c-jun N-terminal kinase (JNK) under oxidative stress conditions, resulting in inhibition of mitochondrial respiration concomitant with enhanced activity of NAD + cleavage. Nonphosphorylatable mutation of Ser-548 or treatment with a JNK inhibitor decreased SARM1 activity. Furthermore, neuronal cells derived from a familial Parkinson's disease (PD) patient showed a congenitally increased level of SARM1 phosphorylation compared with that in neuronal cells from a healthy person and were highly sensitive to oxidative stress. These results indicate that JNK-mediated phosphorylation of SARM1 at Ser-548 is a regulator of SARM1 leading to inhibition of mitochondrial respiration. These findings suggest that an abnormal regulation of SARM1 phosphorylation is involved in the pathogenesis of Parkinson's disease and possibly other neurodegenerative diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
p-Sarm1 (Ser548) accumulates around Aβ plaques in 5xFAD hippocampus.
“We further detected strong accumulation of p-Sarm1 (Ser548), an active form of Sarm1 crucial for NAD + cleavage activity 69 , around Aβ plaques (Fig. 1i), suggesting Sarm1 activation in those sites.”
From NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease (2025) · cites this paper as [69]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Geisler, S., Holmström, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J., & Springer, W. (2010) · Nature Cell Biology · doi:10.1038/ncb2012 · Cited by 2,835 · see citing works
Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C. A., Sou, Y.-S., Saiki, S., Kawajiri, S., Sato, F., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200910140 · Cited by 1,969 · see citing works
Di Lisa, F., Menabò, R., Canton, M., Barile, M., & Bernardi, P. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006825200 · Cited by 678 · see citing works
RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS
Ito, Y., Ofengeim, D., Najafov, A., Das, S., Saberi, S., Li, Y., Hitomi, J., Zhu, H., Chen, H., Mayo, L., et al. (2016) · Science · doi:10.1126/science.aaf6803 · Cited by 606 · see citing works
SARM1 activation triggers axon degeneration locally via NAD <sup>+</sup> destruction
Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A., & Milbrandt, J. (2015) · Science · doi:10.1126/science.1258366 · Cited by 593 · see citing works
Shiba-Fukushima, K., Imai, Y., Yoshida, S., Ishihama, Y., Kanao, T., Sato, S., & Hattori, N. (2012) · Scientific Reports · doi:10.1038/srep01002 · Cited by 577 · see citing works
Flagged first, then by citations
Research works printed but not linked: 35
- Deng, H., Wang, P., and Jankovic, J. (2018) The genetics of Parkinson disease. Ageing Res. Rev. 42, 72-85 CrossRef Medline · DOI · Paper page
- Murata, H., Sakaguchi, M., Jin, Y., Sakaguchi, Y., Futami, J., Yamada, H., Kataoka, K., and Huh, N. H. (2011) A new cytosolic pathway from a Par- kinson disease-associated kinase, BRPK/PINK1: Activation of AKT via mTORC2. J. Biol. Chem. 286, 7182-7189 CrossRef Medline · DOI
- Jin, Y., Murata, H., Sakaguchi, M., Kataoka, K., Watanabe, M., Nasu, Y., Kumon, H., and Huh, N. H. (2012) Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1. Oncol. Rep. 27, 695-699 CrossRef Medline · DOI
- Kane, L. A., Lazarou, M., Fogel, A. I., Li, Y., Yamano, K., Sarraf, S. A., Banerjee, S., and Youle, R. J. (2014) PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 205, 143-153 CrossRef Medline · DOI · Paper page
- Koyano, F., Okatsu, K., Kosako, H., Tamura, Y., Go, E., Kimura, M., Kimura, Y., Tsuchiya, H., Yoshihara, H., Hirokawa, T., Endo, T., Fon, E. A., Trempe, J. F., Saeki, Y., Tanaka, K., and Matsuda, N. (2014) Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510, 162-166 CrossRef Medline · DOI · Paper page
- Gegg, M. E., Cooper, J. M., Chau, K. Y., Rojo, M., Schapira, A. H., and Taanman, J. W. (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum. Mol. Genet. 19, 4861-4870 CrossRef Medline · DOI · Paper page
- Murata, H., Sakaguchi, M., Kataoka, K., and Huh, N. H. (2013) SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria. Mol. Biol. Cell 24, 2772-2784 CrossRef Medline · DOI
- Osterloh, J. M., Yang, J., Rooney, T. M., Fox, A. N., Adalbert, R., Powell, E. H., Sheehan, A. E., Avery, M. A., Hackett, R., Logan, M. A., MacDonald, J. M., Ziegenfuss, J. S., Milde, S., Hou, Y. J., Nathan, C., et al. (2012) dSarm/ Sarm1 is required for activation of an injury-induced axon death pathway. Science 337, 481-484 CrossRef Medline · DOI
- Conforti, L., Gilley, J., and Coleman, M. P. (2014) Wallerian degeneration: An emerging axon death pathway linking injury and disease. Nat. Rev. Neurosci. 15, 394 -409 CrossRef Medline · DOI
- Su, K. G., Banker, G., Bourdette, D., and Forte, M. (2009) Axonal degen- eration in multiple sclerosis: The mitochondrial hypothesis. Curr. Neurol. Neurosci. Rep. 9, 411-417 CrossRef Medline · DOI
- Kanaan, N. M., Pigino, G. F., Brady, S. T., Lazarov, O., Binder, L. I., and Morfini, G. A. (2013) Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system. Exp. Neurol. 246, 44 -53 CrossRef Medline · DOI
- Burke, R. E., and O'Malley, K. (2013) Axon degeneration in Parkinson's disease. Exp. Neurol. 246, 72-83 CrossRef Medline · DOI
- Gerdts, J., Summers, D. W., Sasaki, Y., DiAntonio, A., and Milbrandt, J. (2013) Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J. Neurosci. 33, 13569 -13580 CrossRef Medline · DOI
- Gilley, J., Orsomando, G., Nascimento-Ferreira, I., and Coleman, M. P. (2015) Absence of SARM1 rescues development and survival of NMNAT2-deficient axons. Cell Rep. 10, 1974 -1981 CrossRef Medline · DOI
- Kim, Y., Zhou, P., Qian, L., Chuang, J. Z., Lee, J., Li, C., Iadecola, C., Nathan, C., and Ding, A. (2007) MyD88 -5 links mitochondria, microtu- bules, and JNK3 in neurons and regulates neuronal survival. J. Exp. Med. 204, 2063-2074 CrossRef Medline · DOI · Paper page
- Summers, D. W., DiAntonio, A., and Milbrandt, J. (2014) Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons. J. Neurosci. 34, 9338 -9350 CrossRef Medline · DOI
- Geisler, S., Doan, R. A., Strickland, A., Huang, X., Milbrandt, J., and DiAn- tonio, A. (2016) Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain 139, 3092-3108 CrossRef Medline · DOI
- Gilley, J., Ribchester, R. R., and Coleman, M. P. (2017) Sarm1 deletion, but not Wld(S), confers lifelong rescue in a mouse model of severe axonopa- thy. Cell Rep. 21, 10 -16 CrossRef Medline · DOI
- Henninger, N., Bouley, J., Sikoglu, E. M., An, J., Moore, C. M., King, J. A., Bowser, R., Freeman, M. R., and Brown, R. H., Jr. (2016) Attenuated trau- matic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1. Brain 139, 1094 -1105 CrossRef Medline · DOI
- Vérièpe, J., Fossouo, L., and Parker, J. A. (2015) Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons. Nat. Commun. 6, 7319 CrossRef Medline · DOI
- Panneerselvam, P., Singh, L. P., Ho, B., Chen, J., and Ding, J. L. (2012) Targeting of pro-apoptotic TLR adaptor SARM to mitochondria: defini- tion of the critical region and residues in the signal sequence. Biochem. J. 442, 263-271 CrossRef Medline · DOI
- Summers, D. W., Gibson, D. A., DiAntonio, A., and Milbrandt, J. (2016) SARM1-specific motifs in the TIR domain enable NADϩ loss and regu- late injury-induced SARM1 activation. Proc. Natl. Acad. Sci. U.S.A. 113, E6271-E6280 CrossRef Medline · DOI
- Essuman, K., Summers, D. W., Sasaki, Y., Mao, X., DiAntonio, A., and Milbrandt, J. (2017) The SARM1 Toll/interleukin-1 receptor domain pos- sesses intrinsic NAD(ϩ) cleavage activity that promotes pathological ax- onal degeneration. Neuron 93, 1334 -1343.e1335 CrossRef Medline · DOI · Paper page
- Panneerselvam, P., Singh, L. P., Selvarajan, V., Chng, W. J., Ng, S. B., Tan, N. S., Ho, B., Chen, J., and Ding, J. L. (2013) T-cell death following immune activation is mediated by mitochondria-localized SARM. Cell Death Dif- fer. 20, 478 -489 CrossRef Medline · DOI
- Choi, S. W., Gerencser, A. A., and Nicholls, D. G. (2009) Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram scale: Spare respiratory capacity and stochastic mitochondrial failure. J. Neuro- chem. 109, 1179 -1191 CrossRef Medline · DOI
- Zhang, T., Inesta-Vaquera, F., Niepel, M., Zhang, J., Ficarro, S. B., Machleidt, T., Xie, T., Marto, J. A., Kim, N., Sim, T., Laughlin, J. D., Park, H., LoGrasso, P. V., Patricelli, M., Nomanbhoy, T. K., Sorger, P. K., Alessi, D. R., and Gray, N. S. (2012) Discovery of potent and selective covalent inhibitors of JNK. Chem. Biol. 19, 140 -154 CrossRef Medline · DOI
- Imaizumi, Y., Okada, Y., Akamatsu, W., Koike, M., Kuzumaki, N., Hay- akawa, H., Nihira, T., Kobayashi, T., Ohyama, M., Sato, S., Takanashi, M., Funayama, M., Hirayama, A., Soga, T., Hishiki, T., et al. (2012) Mitochon- drial dysfunction associated with increased oxidative stress and alpha- synuclein accumulation in PARK2 iPSC-derived neurons and postmor- tem brain tissue. Mol. Brain 5, 35 CrossRef Medline · DOI
- Gerdts, J., Summers, D. W., Milbrandt, J., and DiAntonio, A. (2016) Axon self-destruction: New links among SARM1, MAPKs, and NADϩ metab- olism. Neuron 89, 449 -460 CrossRef Medline · DOI
- Yang, J., Wu, Z., Renier, N., Simon, D. J., Uryu, K., Park, D. S., Greer, P. A., Tournier, C., Davis, R. J., and Tessier-Lavigne, M. (2015) Pathological axonal death through a MAPK cascade that triggers a local energy deficit. Cell 160, 161-176 CrossRef Medline · DOI
- Walker, L. J., Summers, D. W., Sasaki, Y., Brace, E. J., Milbrandt, J., and DiAntonio, A. (2017) MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2. eLife 6, e22540 CrossRef Medline · DOI
- Peng, J., Yuan, Q., Lin, B., Panneerselvam, P., Wang, X., Luan, X. L., Lim, S. K., Leung, B. P., Ho, B., and Ding, J. L. (2010) SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. Eur. J. Immunol. 40, 1738 -1747 CrossRef Medline · DOI
- Mukherjee, P., Winkler, C. W., Taylor, K. G., Woods, T. A., Nair, V., Khan, B. A., and Peterson, K. E. (2015) SARM1, not MyD88, mediates TLR7/ TLR9-induced apoptosis in neurons. J. Immunol. 195, 4913-4921 CrossRef Medline · DOI
- Mukherjee, P., Woods, T. A., Moore, R. A., and Peterson, K. E. (2013) Activation of the innate signaling molecule MAVS by bunyavirus infec- tion up-regulates the adaptor protein SARM1, leading to neuronal death. Immunity 38, 705-716 CrossRef Medline · DOI
- Turkiew, E., Falconer, D., Reed, N., and Höke, A. (2017) Deletion of Sarm1 gene is neuroprotective in two models of peripheral neuropathy. J. Pe- ripher. Nerv. Syst. 22, 162-171 CrossRef Medline · DOI
- Sakaguchi, M., Watanabe, M., Kinoshita, R., Kaku, H., Ueki, H., Futami, J., Murata, H., Inoue, Y., Li, S. A., Huang, P., Putranto, E. W., Ruma, I. M., Nasu, Y., Kumon, H., and Huh, N. H. (2014) Dramatic increase in expres- sion of a transgene by insertion of promoters downstream of the cargo gene. Mol. Biotechnol. 56, 621-630 CrossRef Medline · DOI
Cited by
Sorted by citations
NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790 · see citing works
Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases
Hikosaka, K., Yaku, K., Okabe, K., & Nakagawa, T. (2021) · Nutritional Neuroscience · doi:10.1080/1028415x.2019.1637504 · Cited by 62 · see citing works
NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease
Fan, F., Joshi, P., Liu, X., Kotturu, S. K., Abiola, M., Liu, Q., & Lou, X. (2025) · doi:10.64898/2025.12.21.695860
- Authors
- Murata, H., Khine, C. C., Nishikawa, A., Yamamoto, K.-I., Kinoshita, R., & Sakaguchi, M.
- Affiliations
- Okayama University (JP)
- Corresponding author
- Sakaguchi, Masakiyo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 293
- Issue
- 49
- Pages
- 18933-18943
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6295714
- OpenAlex
- W2897689542
- Cited by
- 80
- References
- 6
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 14 · 2022: 16 · 2021: 8 · 2020: 12 · 2019: 9
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- MEXT | Japan Science and Technology Agency (JST) (16K19037)
- Japan Agency for Medical Research and Development (AMED) (JP17km0908001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- SARM1, c-Jun N-terminal kinase, JNK phosphorylation, mitochondrial respiration, oxidative stress, Parkinson's disease, neurodegenerative diseases, axonal degeneration, neuronal cell death
- MeSH terms
- Adenosine Triphosphate, Cytoskeletal Proteins, Humans, Mitochondria, NAD, NAD+ Nucleosidase, Phosphorylation, Serine, Oxidative Stress, Cell Respiration, Cell Line, Tumor, JNK Mitogen-Activated Protein Kinases, Armadillo Domain Proteins, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
