The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation.

Zou R, Shi W, Chang X, Zhang M, Tan S, Li R, Zhou H, Li Y, Wang G, Lv W, Fan X

Theranostics4 Feb 2024Cited by 19 (Europe PMC)

PMID38389837PMCIDPMC10879869DOI10.7150/thno.92650PepBankPUB-38389837

Summary

Rationale: The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promotes pathological mitochondrial fission during septic acute kidney injury. The mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondria-derived peptide that exhibits anti-inflammatory properties during cardiovascular illnesses. We explored whether endotoxemia-induced myocardial microvascular injury involved DNA-PKcs and MOTS-c dysregulation. Methods: To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h. Results: Lipopolysaccharide exposure increased DNA-PKcs activity in cardiac microvascular endothelial cells, while pharmacological inhibition or endothelial cell-specific genetic ablation of DNA-PKcs reduced lipopolysaccharide-induced myocardial microvascular dysfunction. Proteomic analyses showed that endothelial DNA-PKcs ablation primarily altered mitochondrial protein expression. Verification assays confirmed that DNA-PKcs drastically repressed MOTS-c transcription by inducing mtDNA breaks via pathological mitochondrial fission. Inhibiting MOTS-c neutralized the endothelial protective effects of DNA-PKcs ablation, whereas MOTS-c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress. In molecular studies, MOTS-c downregulation disinhibited c-Jun N-terminal kinase (JNK), allowing JNK to phosphorylate profilin-S173. Inhibiting JNK or transfecting cells with a profilin phosphorylation-defective mutant improved endothelial barrier function by preventing F-actin depolymerization and lamellipodial degradation following lipopolysaccharide treatment. Conclusions: DNA-PKcs inactivation during endotoxemia could be a worthwhile therapeutic strategy to restore MOTS-c expression, prevent JNK-induced profilin phosphorylation, improve F-actin polymerization, and enhance lamellipodial integrity, ultimately ameliorating endothelial barrier function and reducing myocardial microvascular injury.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study5

2 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In an endotoxemia model, MOTS‑c supplementation enhanced endothelial barrier function under lipopolysaccharide stress.
In plain wordsIn mice, MOTS‑c supplementation improved the barrier function of blood-vessel lining cells under lipopolysaccharide stress.
Peptide
MOTS-c
Outcome
IncreaseEndothelial barrier function under lipopolysaccharide stress
Study
mousen: not reported in source
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
MOTS-c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress.
1 context sentence(design, population, supporting numbers)
Summary · context
To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h.
Show in the study text Report a problemFND-3838983701
02AnimalAnimal study (in vivo)Efficacy outcome
In an endotoxemia model, MOTS‑c supplementation enhanced myocardial microvascular homeostasis under lipopolysaccharide stress.
In plain wordsIn mice, MOTS‑c supplementation improved the balance of small heart blood vessels under lipopolysaccharide stress.
Peptide
MOTS-c
Outcome
IncreaseMyocardial microvascular homeostasis under lipopolysaccharide stress
Study
mousen: not reported in source
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
MOTS-c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress.
1 context sentence(design, population, supporting numbers)
Summary · context
To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h.
Show in the study text Report a problemFND-3838983702

Natural levels measured1

These results measure the body's own peptide. Nobody was given the peptide. They are not evidence about taking it. They are left out of key results, evidence counts and charts.

03AnimalEndogenous levelAnimal study (in vivo)Mechanism
In an endotoxemia model, DNA-PKcs repressed the body's own MOTS‑c transcription by inducing mtDNA breaks via pathological mitochondrial fission.
In plain wordsIn mice, DNA-PKcs lowered the body's own MOTS‑c production in heart blood-vessel cells.
Peptide
MOTS-c
Outcome
DecreaseMOTS-c transcription repressed by DNA-PKcs
Study
mousen: not reported in source
Outcome group
Mitochondrial function · Cardiovascular
Source sentences
Summary
Verification assays confirmed that DNA-PKcs drastically repressed MOTS-c transcription by inducing mtDNA breaks via pathological mitochondrial fission.
1 context sentence(design, population, supporting numbers)
Summary · context
To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h.
This result measures the body's own MOTS-c. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-3838983703

Studies that did not test the peptide alone2

In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking MOTS-c.

04AnimalNot a test of MOTS-c aloneAnimal study (in vivo)Mechanism
In an endotoxemia model, inhibiting MOTS‑c neutralized the endothelial protective effects of DNA-PKcs ablation.
In plain wordsIn mice, blocking the body's own MOTS‑c removed the blood-vessel protection that came from removing DNA-PKcs.
Peptide
MOTS-c
Outcome
DecreaseEndothelial protection from DNA-PKcs ablation after MOTS-c inhibition
Study
mousen: not reported in source
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
Inhibiting MOTS-c neutralized the endothelial protective effects of DNA-PKcs ablation
1 context sentence(design, population, supporting numbers)
Summary · context
To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-3838983704
05AnimalNot a test of MOTS-c aloneAnimal study (in vivo)Mechanism
In molecular studies, MOTS‑c downregulation disinhibited JNK, which then phosphorylated profilin-S173.
In plain wordsIn lab studies, lower MOTS‑c levels freed the JNK enzyme to add a phosphate group to the profilin protein.
Peptide
MOTS-c
Outcome
IncreaseJNK activity and profilin-S173 phosphorylation after MOTS-c downregulation
Study
mousen: not reported in source
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
In molecular studies, MOTS-c downregulation disinhibited c-Jun N-terminal kinase (JNK), allowing JNK to phosphorylate profilin-S173.
1 context sentence(design, population, supporting numbers)
Summary · context
To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-3838983705

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
9 Oct 2026, 18:17 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

PepBank is a research reference. Talk to a doctor before you use any peptide.