Mots-C
Mitochondrial open reading frame of the 12S rRNA-c, MT-RNR1, Mitochondrial-derived peptide MOTS-c
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. Rongjun R; Shi. Wanting W; Chang. Xing X; Zhang. Miao M; Tan. Songtao S; Li. Ruibing R; Zhou. Hao H; Li. Yukun Y; Wang. Ge G; Lv. Weihui W; Fan. Xiaoping X
Key Findings
- Endotoxin exposure boosts DNA‑PKcs activity in heart microvascular endothelial cells, which dramatically cuts MOTS‑c production by causing mitochondrial DNA damage.
- Genetic removal of DNA‑PKcs or pharmacological inhibition restores MOTS‑c levels and improves endothelial barrier function, reducing microvascular injury.
- MOTS‑c protects cells by preventing JNK activation; when JNK is active it phosphorylates profilin, leading to actin breakdown and loss of lamellipodia, but MOTS‑c supplementation blocks this cascade.
Practical Outcomes
- For biohackers, the data suggest that MOTS‑c supplementation could help maintain vascular health during acute inflammatory stress, acting as an anti‑inflammatory and barrier‑supporting agent. Direct DNA‑PKcs inhibition isn’t yet a realistic DIY approach, so the main actionable takeaway is the potential benefit of MOTS‑c, though human trials are needed before routine use.
Summary
The study shows that during severe inflammation (like sepsis), a protein called DNA‑PKcs shuts down the production of the mitochondrial peptide MOTS‑c, which then leads to damage in tiny heart blood vessels. Blocking DNA‑PKcs or giving extra MOTS‑c protects those vessels by keeping a stress‑signal pathway (JNK) turned off and preserving the cell’s internal scaffolding.
Abstract
<b>Rationale:</b> 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. <b>Methods:</b> To induce endotoxemia <i>in vivo,</i> endothelial cell-specific <i>DNA-PKcs-</i>knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h. <b>Results:</b> Lipopolysaccharide exposure increased DNA-PKcs activity in cardiac microvascular endothelial cells, while pharmacological inhibition or endothelial cell-specific genetic ablation of <i>DNA-PKcs</i> reduced lipopolysaccharide-induced myocardial microvascular dysfunction. Proteomic analyses showed that endothelial <i>DNA-PKcs</i> ablation primarily altered mitochondrial protein expression. Verification assays confirmed that DNA-PKcs drastically repressed <i>MOTS-c</i> transcription by inducing mtDNA breaks via pathological mitochondrial fission. Inhibiting <i>MOTS-c</i> neutralized the endothelial protective effects of <i>DNA-PKcs</i> 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. <b>Conclusions:</b> 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.
Study Information
pubmed
2024
2024-02-04T00:00:00.000Z
10.7150/thno.92650
12
76