Dpep1 Mediates Regulation of Mitochondrial Quality Control Via Foxo1 to Attenuate Ferroptosis in Pulmonary Endothelial Cells to Attenuate Sali and the Protective Effect of the Mitochondria-Derived Peptide Mots-C

Abstract

Sepsis is a common cause of acute lung injury and acute respiratory distress syndrome. Results from both in vitro and in vivo experiments demonstrate that knockdown of DPEP1 attenuated LPS-induced inflammation, ferroptosis, and oxidative stress in lung endothelial cells. In LPS-treated HPMVECs, DPEP1 knockdown preserved mitochondrial quality control (MQC), as evidenced by a shift from mitochondrial fission to fusion, reduced mitophagy, and enhanced fatty acid oxidation (FAO). Mechanistically, DPEP1 knockdown restored FOXO1 expression and increased ALDH1L2 levels, thereby improving FAO and preserving MQC, alleviating ferroptosis and oxidative stress. Inhibition of FOXO1 with AS18 reversed these protective effects. Additionally, Mdivi-1, 3-MA, and MOTS-c synergistically inhibited ferroptosis and oxidative stress when combined with DPEP1 knockdown. Overall, DPEP1 regulates MQC via the FOXO1/ALDH1L2 to alleviate ferroptosis. Mdivi-1, 3-MA, and MOTS-c synergistically target DPEP1, further alleviating Sepsis-associated Acute Lung Injury (SALI) and showing potential as protective treatments against SALI.

Note:
Funding declaration: The research was funded by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (JX10214182, JX54814380), the Key Project of Taizhou School of Clinical Medicine (No. TZKY20220304), the Yili & Jiangsu Joint Institute of Health (No. YL2022MS04), the Science Foundation Project of Yili & Jiangsu Joint Institute of Health (grant number: ly2023zd01), the 2023th Nanjing Medical University First Affiliated Hospital's National Natural Science Foundation of China Youth Fund Cultivation Program (PY2023022).

Conflict of Interests: There are no conflicts of interest to declare.

Ethical Approval: This study's animal experiments were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (Approval Number IACUC-2407067).

Keywords: Sepsis-associated Acute lung injury, DPEP1, Forkhead box O1, Mitochondrial quality control