Hepatology | Wuhan University's Song Quyin et al. team discovers a new mechanism of mitochondrial DNA release

Sam50 is a key component of the Sorting and Assembly Machine (SAM) complex and is also involved in bridging the mitochondrial outer and inner membrane contacts. However, the physiological and pathological functions of Sam50 remain largely unknown.

March 21, 2022, Wuhan University, Song Quyin and Meng Qingtao co-communication inHepatology(IF=17) published online a study entitled "Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release Loss of Sam50 leads to mtDNA aggregation. In addition, Sam50 cooperates with Mic60 to bind cardiolipin and maintain mitochondrial membrane integrity, and Sam50 depletion leads to cardiolipin externalization, which results in remodeling of the outer and inner mitochondrial membranes, including the cristae, triggering Bax mitochondrial recruitment, mtDNA aggregation and release.

Physiologically, acetaminophen (APAP, a potent antipyretic and analgesic) induced Sam50 reduction or Sam50 liver-specific knockdown induces mtDNA release, leading to activation of the cGAS-STING pathway and liver inflammation in mice. In addition, exogenous expression of Sam50 significantly attenuated APAP-induced hepatotoxicity. Thus, the results of this study reveal a critical role of Sam50 in maintaining hepatocyte mitochondrial membrane integrity and mtDNA stability, and reveal that Sam50 depletion-induced cardiolipin externalization is a novel signal for mtDNA release and controls mtDNA-dependent innate immunity.

Hepatology | Wuhan University's Song Quyin et al. team discovers a new mechanism of mitochondrial DNA release

Mitochondria are highly dynamic double-membrane organelles containing mitochondrial DNA (mtDNA), which encodes a key subunit of the mitochondrial respiratory chain complex and is essential for ATP production. sam50 (or Samm50) is a key component of the sorting and assembly machinery (SAM) necessary for β-barrel protein assembly in the outer mitochondrial membrane, which regulates mitochondrial morphology and cristae structure. In addition, Sam50 binds to the MICOS complex to form the supercomplex BIM, which links the outer and inner mitochondrial membranes. Interestingly, Sam50 depletion induces PINK1-Parkin-dependent mitochondrial autophagy, but leads to mtDNA aggregation, which protects mtDNA from removal by mitochondrial autophagy. Furthermore, polymorphisms in the Sam50 gene are significantly associated with the development and progression of NAFLD. However, the role of Sam50 in the regulation of mtDNA and the relationship between Sam50 and human diseases remain unclear.

Unlike nuclear DNA, mtDNA lacks protective histones and is particularly susceptible to attack by mitochondrial damage factors, such as ROS. Damaged or stressed mtDNA can be released from the mitochondria into the cytoplasm. Recently, many studies have reported on the mechanism of mtDNA release. During apoptosis, Bax oligomerizes with Bak and forms extremely large pores in the outer mitochondrial membrane, which mediates the release of mtDNA. In addition, mitochondria subjected to oxidative stress release short mtDNA fragments through pores formed by VDAC oligomers in the outer mitochondrial membrane. In addition, mitochondrial permeability transition pores located in the inner mitochondrial membrane may be involved in the release of mtDNA. However, the signaling and underlying mechanisms of mtDNA release are still poorly understood.

In response to various infections, cyclic GMP-AMP (cGAMP) synthase (cGAS) acts as a cytosolic DNA sensor, activating the innate immune response by producing the second messenger cGAMP, which activates the junction STING. activated STING then recruits and activates TBK1, which phosphorylates STING and IRF3 to induce type I IFN and many other The production of IFN and many other pro-inflammatory cytokines. In addition, TBK1 activity is regulated by Ser-172 phosphorylation within the kinase activation loop. In addition to pathogen-derived DNA from microbial infections, the cGAS-STING pathway can also be activated by cytosolic mtDNA. In addition, cytoplasmic mtDNA activates TLR9 or inflammatory vesicle-mediated signaling pathways.

Hepatology | Wuhan University's Song Quyin et al. team discovers a new mechanism of mitochondrial DNA release

Article mode diagram (image fromHepatology)

Cardiolipin is a unique dimeric phospholipid that is found primarily within the inner mitochondrial membrane to maintain the integrity of the mitochondrial membrane. Cardiolipin is required for several key mitochondrial processes, including mitochondrial respiration, mitochondrial dynamics, apoptosis and mitochondrial autophagy. Cardiolipin interacts directly with the mitochondrial respiratory chain complex and stabilizes it to regulate the production of ATP. Cardiolipin serves as a key signaling platform for initiating apoptosis and mitochondrial autophagy, it is exposed to the outer mitochondrial membrane (cardiolipin externalization) in response to many mitochondrial stresses, and externalized cardiolipin promotes Bax or Bak oligomerization to induce large membrane pores and binds to LC3 to trigger mitochondrial autophagy .

Acetaminophen (APAP) is an effective antipyretic and analgesic, but overdose of APAP is the most common drug poisoning and the leading cause of acute liver failure worldwide.APAP overdose leads to excessive excretion of the intermediate metabolite N-acetyl-p-benzoquinoneimine (NAPQI) from glutathione (GSH), resulting in covalent binding of sulfhydryl groups in cellular proteins, particularly mitochondrial proteins, which This leads to mitochondrial oxidative stress, dysfunction, and ultimately hepatocyte necrosis and liver injury. Although there is growing evidence for a role of mitochondria in APAP-induced liver injury, the mechanism by which APAP leads to DAMP (damage-associated molecular pattern) release and subsequent liver injury remains unclear.

Here, this study shows that Sam50 depletion or APAP treatment leads to mtDNA release through the Bax/Bak mitochondrial pore, which then activates the cGAS-STING signaling pathway and liver inflammation in mice. Importantly, this study found that Sam50 depletion induced cardiolipin externalization, leading to Bax mitochondrial recruitment and ultimately triggering mtDNA release. Thus, the results of this study suggest that Sam50 depletion-induced cardiolipin externalization is a novel signal for mtDNA release.

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