期刊
EMBO JOURNAL
卷 41, 期 24, 页码 -出版社
WILEY
DOI: 10.15252/embj.2022111173
关键词
MIMP; mtDNA; PHB; SPG7
资金
- NSFC [32170758, 31771531]
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (GDUPS, 2018)
- Sixth Affiliated Hospital of the Guangzhou Medical University
- Qingyuan People's Hospital
- Guangzhou Ling Nan Ying Cai Project 2018
- Chuang Xin Qiang Xiao project of the Guangzhou Medical University [2019KCXTD015]
- National Natural Science Foundation of China [82001205, 82170461]
- Natural Science Foundation of Guangdong [2020A1515010022]
- Fundamental and Applied Fundamental Research Project of Guangzhou [202102020016]
This study reveals the critical role of the inner mitochondrial membrane protein PHB1 in regulating permeability and integrity of mitochondria. Loss of PHB1 leads to alterations in mitochondrial function and increased release of mtDNA, resulting in enhanced inflammatory responses. Inflammatory stresses downregulate PHB1 expression, leading to increased mtDNA release and inflammation.
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-1 beta (IL-1 beta) 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.
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