Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 18933-18943 |
| Number of pages | 11 |
| Journal | Journal of Biological Chemistry |
| Volume | 293 |
| Issue number | 49 |
| DOIs | |
| Publication status | Published - Jan 1 2018 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
C-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD cleavage activity to inhibit mitochondrial respiration. / Murata, Hitoshi; Khine, Cho Cho; Nishikawa, Akane; Yamamoto, Ken-ichi; Kinoshita, Rie; Sakaguchi, Masakiyo.
In: Journal of Biological Chemistry, Vol. 293, No. 49, 01.01.2018, p. 18933-18943.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - C-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD cleavage activity to inhibit mitochondrial respiration
AU - Murata, Hitoshi
AU - Khine, Cho Cho
AU - Nishikawa, Akane
AU - Yamamoto, Ken-ichi
AU - Kinoshita, Rie
AU - Sakaguchi, Masakiyo
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85058161710&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.004578
DO - 10.1074/jbc.RA118.004578
M3 - Article
C2 - 30333228
AN - SCOPUS:85058161710
VL - 293
SP - 18933
EP - 18943
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 49
ER -