2. Academic Validation
  3. Prohibitin 1 regulates mtDNA release and downstream inflammatory responses

Prohibitin 1 regulates mtDNA release and downstream inflammatory responses

  • EMBO J. 2022 Oct 17;e111173. doi: 10.15252/embj.2022111173.
Hao Liu # 1 2 3,  Hualin Fan # 2 4,  Pengcheng He # 5 6 7 8,  Haixia Zhuang 9,  Xiao Liu 2,  Meiting Chen 10,  Wenwei Zhong 2,  Yi Zhang 2 11,  Cien Zhen 2 4,  Yanling Li 10,  Huilin Jiang 10,  Tian Meng 2,  Yiming Xu 1 2 3,  Guojun Zhao 1,  Du Feng 1 2 3
Affiliations

Affiliations

  • 1 Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China.
  • 2 Guangzhou Municipal and Guangdong Provincial Key hLaboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
  • 4 Department of Cardiology, School of Medicine, South China University of Technology, Guangzhou, China.
  • 5 Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 6 Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 7 Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.
  • 8 Department of Cardiology, Heyuan People's Hospital, Heyuan, China.
  • 9 Department of Anesthesiology, Second Clinical College of Guangzhou Medical University, Guangzhou, China.
  • 10 Emergency Department, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 11 GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China.
  • # Contributed equally.
PMID: 36245295 DOI: 10.15252/embj.2022111173
Abstract

Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1-deficient macrophages, serum from myeloid-specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin-1β (IL-1β) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1-depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT-4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.

Keywords

AFG3L2; MIMP; PHB; SPG7; mtDNA.

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