Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury.

BACKGROUND AND AIMS: Sam50, a key component of the sorting and assembly machinery (SAM) complex, is also involved in bridging mitochondrial outer-membrane and inner-membrane contacts. However, the physiological and pathological functions of Sam50 remain largely unknown. APPROACH AND RESULTS: Here we show that Sam50 interacts with MICOS (mitochondrial contact site and cristae organizing system) and ATAD3 (ATPase family AAA domain-containing protein 3) to form the Sam50-MICOS-ATAD3-mtDNA axis, which maintains mtDNA stability. Loss of Sam50 causes mitochondrial DNA (mtDNA) aggregation. Furthermore, Sam50 cooperates with Mic60 to bind to cardiolipin, maintaining the integrity of mitochondrial membranes. Sam50 depletion leads to cardiolipin externalization, which causes mitochondrial outer-membrane and inner-membrane (including crista membrane) remodeling, triggering Bax mitochondrial recruitment, mtDNA aggregation, and release. Physiologically, acetaminophen (an effective antipyretic and analgesic)-caused Sam50 reduction or Sam50 liver-specific knockout induces mtDNA release, leading to activation of the cGAS-STING pathway and liver inflammation in mice. Moreover, exogenous expression of Sam50 remarkably attenuates APAP-induced liver hepatoxicity. CONCLUSIONS: Our findings uncover the critical role of Sam50 in maintaining mitochondrial membrane integrity and mtDNA stability in hepatocytes and reveal that Sam50 depletion-induced cardiolipin externalization is a signal of mtDNA release and controls mtDNA-dependent innate immunity.

[Efficacy of electroacupuncture nerve stimulation therapy for interstitial cystitis/bladder pain syndrome].

OBJECTIVE: To explore the clinical efficacy of electroacupuncture nerve stimulation therapy (ENST) for interstitial cystitis/painful bladder syndrome (IC/PBS). METHODS: A total of 68 patients with IC/PBS were randomly divided into an observation group and a control group, 34 cases in each one. The patients in the observation group were treated with ENST; abdominal four acupoints and sacral four acupoints were connected with a pair of electrodes and treated alternately every other day. The ENST was given 50 min per times, three times a week for 3 months. The patients in the control group were treated with perfusion therapy of four-medication combination (heparin sodinm, lidocaine, sodium bicarbonate, gentamicin sulfate), twice a week for the first 6-8 weeks, followed by twice per month for 3 months. The infusion fluid remained for 1 h before discharging. The O' Leary-Sant score, including interstitial cystitis symptom index (ICSI) and interstitial cystitis problem index (ICPI), 24 h urination frequency, visual analogue scale (VAS) and maximum bladder volume were observed before treatment and treatment of 1 month, 3 months and 6 months after treatment respectively; the adverse events during the treatment were also recorded. RESULTS: Compared before treatment, the O'Leary-Sant score (ICSI, ICPI), 24 h urination frequency, VAS and maximum bladder volume in the two groups were improved after 1, 3 months treatment and 6 months after treatment (all P<0.05). The scores of ICSI, ICPI, VAS and 24 h urination frequency in the observation group were significantly lower than those in the control group (P<0.05). The maximum bladder volume in the observation group was significantly higher than that in the control group (P<0.05). Six months after treatment, the total effective rate in the observation group was 87.5% (28/32), which was higher than 69.7% (23/33) in the control group (P<0.01). No significant adverse events occurred during the treatment. CONCLUSION: ENST could effectively relieve the clinical symptoms of IC/PBS, but its long-term efficacy needs further observation.

A small molecule emitting in the near infrared region with pH sensitivity for visualization mitochondria under super-resolution microscopy.

Small molecules emitting in the NIR for tracking mitochondrial pH alteration with super-resolution are expected to play an essential role in biomedical applications. Herein, two small molecules based on pyridinium salt (P1 and P2) have been synthesized and systematically investigated. It was found that pyridinium salts P1 and P2 emitted in the NIR (about 610 nm), which could detect pH changes from 2.0 to 11.0 with good linearity and high sensitivity. Importantly, P2 could precisely target cellular mitochondria in a real-time manner under stimulated emission depletion (STED). These results implied a chemical strategy with a potential application in super-resolution imaging and mitochondrial pH determination.