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Mol Cell Biol. 2017 Sep 26;37(20). pii: e00354-17. doi: 10.1128/MCB.00354-17. Print 2017 Oct 15.

Acylation of Superoxide Dismutase 1 (SOD1) at K122 Governs SOD1-Mediated Inhibition of Mitochondrial Respiration.

Author information

1
Department of Chemistry and Biochemistry, Fritz B. Burns Cancer Research Laboratory, Brigham Young University, Provo, Utah, USA.
2
School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA.
3
The Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina, USA.
4
School of Chemistry and Biochemistry and Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia, USA.
5
Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, Utah, USA.
6
Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, USA.
7
Department of Chemistry and Biochemistry, Fritz B. Burns Cancer Research Laboratory, Brigham Young University, Provo, Utah, USA jandersen@chem.byu.edu.

Abstract

In this study, we employed proteomics to identify mechanisms of posttranslational regulation on cell survival signaling proteins. We focused on Cu-Zn superoxide dismutase (SOD1), which protects cells from oxidative stress. We found that acylation of K122 on SOD1, while not impacting SOD1 catalytic activity, suppressed the ability of SOD1 to inhibit mitochondrial metabolism at respiratory complex I. We found that deacylase depletion increased K122 acylation on SOD1, which blocked the suppression of respiration in a K122-dependent manner. In addition, we found that acyl-mimicking mutations at K122 decreased SOD1 accumulation in mitochondria, initially hinting that SOD1 may inhibit respiration directly within the intermembrane space (IMS). However, surprisingly, we found that forcing the K122 acyl mutants into the mitochondria with an IMS-targeting tag did not recover their ability to suppress respiration. Moreover, we found that suppressing or boosting respiration levels toggled SOD1 in or out of the mitochondria, respectively. These findings place SOD1-mediated inhibition of respiration upstream of its mitochondrial localization. Lastly, deletion-rescue experiments show that a respiration-defective mutant of SOD1 is also impaired in its ability to rescue cells from toxicity caused by SOD1 deletion. Together, these data suggest a previously unknown interplay between SOD1 acylation, metabolic regulation, and SOD1-mediated cell survival.

KEYWORDS:

superoxide dismutase

PMID:
28739857
PMCID:
PMC5615182
DOI:
10.1128/MCB.00354-17
[Indexed for MEDLINE]
Free PMC Article

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