Mitochondria are multifunctional organelles that produce energy and are critical for various signaling pathways. Mitochondrial antiviral signaling (MAVS) is a mitochondrial outer membrane protein essential for the anti-RNA viral immune response, which is regulated by mitochondrial dynamics and energetics; however, the molecular link between mitochondrial metabolism and immunity is unclear. Here we show in cultured mammalian cells that MAVS is activated by mitochondrial fission factor (Mff), which senses mitochondrial energy status. Mff mediates the formation of active MAVS clusters on mitochondria, independent of mitochondrial fission and dynamin-related protein 1. Under mitochondrial dysfunction, Mff is phosphorylated by the cellular energy sensor AMP-activated protein kinase (AMPK), leading to the disorganization of MAVS clusters and repression of the acute antiviral response. Mff also contributes to immune tolerance during chronic infection by disrupting the mitochondrial MAVS clusters. Taken together, Mff has a critical function in MAVS-mediated innate immunity, by sensing mitochondrial energy metabolism via AMPK signaling.

The protein known as Spred1 (Sprouty‐related Ena/VASP homology‐1 domain‐containing protein) has been identified as a negative regulator of growth factor‐induced ERK/mitogen‐activated protein kinase activation. Spred1 has also been implicated as the target of microRNA‐126 (miR126), a miRNA located within the Egfl7 gene, and is involved in the regulation of vessel development through its role in regulating VEGF signaling. In this study, we examined the role of miR126 and Spred1 in the hematopoietic system, as miR126 has been shown to be overexpressed in leukemic cells. miR126 levels were down‐regulated during mast cell differentiation from bone marrow cells, whereas Spred1 expression was inversely up‐regulated. Overexpression of miR126 suppressed Spred1 expression and enhanced ERK activity in primary bone marrow cells and MC9 mast cells, which were associated with elevated FcεRI‐mediated cytokine production. To confirm the effect of Spred1 reduction in vivo, we generated hematopoietic cell‐specific Spred1‐conditional knockout mice. These mice showed increased numbers of mast cells, and Spred1‐deficient bone marrow‐derived mast cells were highly activated by cross‐linking of Fcε‐R stimulation as well as by IL‐3 and SCF stimulation. These results suggest that Spred1 negatively regulates mast cell activation, which is modulated by miR126.

Context 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing’s syndrome (CS) and autonomous cortisol secretion (ACS) patients. Objective To confirm the efficacy and safety of S-707106 (11β-HSD1 inhibitor) administered to CS and ACS patients. Design A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database. Setting Kyushu University Hospital, Kurume University Hospital, and related facilities. Patients Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance. Intervention Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks. Main Outcome Measures The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks. Results S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by −7.1% [SD, 14.8 (90% CI −14.8 to −1.0), P = 0.033] and −2.7% [14.5 (−10.2 to 3.4), P = 0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by −2.5% [1.7 (−3.3 to −1.8), P < 0.001] and body muscle percentage increased by 2.4% [1.6 (1.7 to 3.1), P < 0.001]. Conclusions S-707106 is an effective insulin sensitizer and antisarcopenic and antiobesity medication for these patients.

Proteostasis maintains protein homeostasis and participates in regulating critical cardiometabolic disease risk factors including proprotein convertase subtilisin/kexin type 9 (PCSK9). Endoplasmic reticulum (ER) remodeling through release and incorporation of trafficking vesicles mediates protein secretion and degradation. We hypothesized that ER remodeling that drives mitochondrial fission participates in cardiometabolic proteostasis. We used in vitro and in vivo hepatocyte inhibition of a protein involved in mitochondrial fission, dynamin-related protein 1 (DRP1). Here, we show that DRP1 promotes remodeling of select ER microdomains by tethering vesicles at ER. A DRP1 inhibitor, mitochondrial division inhibitor 1 (mdivi-1) reduced ER localization of a DRP1 receptor, mitochondrial fission factor, suppressing ER remodeling-driven mitochondrial fission, autophagy, and increased mitochondrial calcium buffering and PCSK9 proteasomal degradation. DRP1 inhibition by CRISPR/Cas9 deletion or mdivi-1 alone or in combination with statin incubation in human hepatocytes and hepatocyte-specific Drp1-deficiency in mice reduced PCSK9 secretion (−78.5%). In HepG2 cells, mdivi-1 increased low-density lipoprotein receptor via c-Jun transcription and reduced PCSK9 mRNA levels via suppressed sterol regulatory binding protein-1c. Additionally, mdivi-1 reduced macrophage burden, oxidative stress, and advanced calcified atherosclerotic plaque in aortic roots of diabetic Apoe-deficient mice and inflammatory cytokine production in human macrophages. We propose a novel tethering function of DRP1 beyond its established fission function, with DRP1-mediated ER remodeling likely contributing to ER constriction of mitochondria that drives mitochondrial fission. We report that DRP1-driven remodeling of select ER micro-domains may critically regulate hepatic proteostasis and identify mdivi-1 as a novel small molecule PCSK9 inhibitor.