Optic atrophy 1 (OPA1) is a mitochondrial inner membrane protein that has an important role in mitochondrial fusion and structural integrity. Dysfunctional OPA1 mutations cause atrophy of the optic nerve leading to blindness. Here, we show that OPA1 has an important role in the innate immune system. Using conditional knockout mice lacking Opa1 in neutrophils (Opa1^N∆), we report that lack of OPA1 reduces the activity of mitochondrial electron transport complex I in neutrophils. This then causes a decline in adenosine-triphosphate (ATP) production through glycolysis due to lowered NAD⁺availability. Additionally, we show that OPA1-dependent ATP production in these cells is required for microtubule network assembly and for the formation of neutrophil extracellular traps. Finally, we show thatOpa1^N∆mice exhibit a reduced antibacterial defense capability againstPseudomonas aeruginosa.

Non-alcoholic fatty liver disease (NAFLD) leads to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. For sedentary patients, lifestyle interventions combining exercise and dietary changes are a cornerstone of treatment. However, the benefit of exercise alone when dietary changes have failed is uncertain. We query whether exercise alone arrests the progression of NASH and tumorigenesis in a choline-deficient, high-fat diet (CD-HFD) murine model. Male C57Bl/6N mice received a control diet or CD-HFD for 12 weeks. CD-HFD mice were randomized further for 8 weeks of sedentariness (SED) or treadmill exercise (EXE). CD-HFD for 12 weeks produced NAFL. After 20 weeks, SED mice developed NASH and hepatic adenomas. Exercise attenuated the progression to NASH. EXE livers showed lower triglycerides and tumor necrosis factor-α expression, less fibrosis, less ballooning, and a lower NAFLD activity score than did SED livers. Plasma transaminases and triglycerides were lower. Exercise activated AMP-activated protein kinase (AMPK) with inhibition of mTORC1 and decreased S6 phosphorylation, reducing hepatocellular adenoma. Exercise activated autophagy with increased LC3-II/LC3-I and mitochondrial recruitment of phosphorylated PTEN-induced kinase. Therefore, exercise attenuates the transition from NAFL to NASH, improves biochemical and histological parameters of NAFLD, and impedes the progression of fibrosis and tumorigenesis associated with enhanced activation of AMPK signaling and favors liver autophagy. Our work supports the benefits of exercise independently of dietary changes.

The role of mitochondria in steroidogenesis is well established. However, the specific effects of mitochondrial dysfunction on androgen synthesis are not fully understood. In this study, we investigate the effects of various mitochondrial and metabolic inhibitors in H295R adrenal cells and perform a comprehensive analysis of steroid and metabolite profiling. We report that mitochondrial complex I inhibition by rotenone shifts cells toward anaerobic metabolism with a concomitant hyperandrogenic phenotype characterized by rapid stimulation of dehydroepiandrosterone (DHEA, 2 h) and slower accumulation of androstenedione and testosterone (24 h). Screening of metabolic inhibitors confirmed DHEA stimulation, which included mitochondrial complex III and mitochondrial pyruvate carrier inhibition. Metabolomic studies revealed truncated tricarboxylic acid cycle with an inverse correlation between citric acid and DHEA production as a common metabolic marker of hyperandrogenic inhibitors. The current study sheds light on a direct interplay between energy metabolism and androgen biosynthesis that could be further explored to identify novel molecular targets for efficient treatment of androgen excess disorders.

T helper 9 cells (T _H 9) are key drivers of allergic tissue inflammation. They are characterized by the expression of type 2 cytokines, such as IL-9 and IL-13, and the peroxisome proliferator-activated receptor gamma (PPAR-γ) transcription factor. However, the functional role of PPAR-γ in human T _H 9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, specifically promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments on skin samples of allergic contact dermatitis showed that the PPAR-γ-mTORC1-IL-9 pathway was active in T _H 9 cells in human skin inflammation. Additionally, we found that tissue glucose levels were dynamically regulated in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological signals in vivo. Furthermore, paracrine IL-9 induced the lactate transporter MCT1 in IL-9R ⁺ T _H cells, where it increased aerobic glycolysis and proliferative capacity. Taken together, our findings delineate a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and the pathogenic effector function of human T _H 9 cells. Graphical

A 3-year-old previously healthy Caucasian boy with a history of non-weight bearing since one week presented to our emergency department. The parents did not report pain at night or at rest or fever. He had suffered from spontaneous gingival bleedings for several days and intermittent nose bleedings for several months. A detailed dietary history revealed a fussy eater with a restricted diet entirely based on cow’s milk with dissolved cookies. He was growing appropriately on the 75^th percentile. His parents and siblings were well. Clinical examination revealed spontaneously semiflexed hips and knees and, bilateral swelling of knees with no appreciable effusion. He had bilateral leg weakness with unwillingness to move his knees or hips with painful but full passive range of movement. He walked with a limp, and could not stand up without support or climb the stairs. The muscular reflexes of the lower limbs were normal. He presented multiple small petechiae on the legs, swollen gums with multiple haemorrhages and spontaneous gingival bleeding at the gingival line ([Fig. 1]). Vital parameters were normal. Laboratory evaluation revealed slightly elevated inflammatory markers (c-reactive protein 13 mg/L, blood sedimentation rate 23 mm/h) and severe vitamin D deficiency (<25 nmol/L). Apart from hypochromic microcytic red blood cells (MCV 69 fL, MCH 24 pg) his blood film was normal (Hb 113 g/L, Ery 4.78 T/L, WBC 10.7 G/L, Plt 299 G/L). He had normal creatine kinase (77 U/L) and coagulation status (INR 1.06, aPTT 29.7 sec). Sonographically there was no evidence of a hip or knee joint effusion. The radiograph of the backbone showed no evidence of tumorous change or fracture. An MRI of the spine, pelvis and proximal lower extremities revealed multiple osseous hyperintense lesions within both proximal femur metaphyses, the right acetabulum, os ischium and right distal femur metaphysis and signs of subperiosteal hemorrhage ([Fig. 2]). Initial differential diagnosis was broad and included osteomyelitis, spondilitis, muscular origin, rheumatological disease, or metabolic bone disease. He was admitted to hospital for a trial of analgesia, which showed minimal response. After interdisciplinary discussion, the clinical findings combined with the restricted diet and MRI patterns led to the suspicion of a severe nutritive vitamin C deficiency, which was confirmed by an undetectable vitamin C level (<5 µmol/l, normal range 26–97 µmol/l). An empirical treatment with 200 mg oral vitamin C daily was started, which led to a full recovery of gingival hyperplasia and bleeding within three days and improvement of walking within five days. For his feeding difficulties the boy was enrolled in a feeding program and was discharged from the hospital after two weeks. After four weeks of supplementation vitamin C level returned to normal (61.3 μmol/l) and supplementation was successfully discontinued. Article published online: 27 February 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany