Mitochondria are essential metabolic hubs that dynamically adapt to physiological demands. More than 40 proteases residing in different compartments of mitochondria, termed mitoproteases, preserve ...mitochondrial proteostasis and are emerging as central regulators of mitochondrial plasticity. These multifaceted enzymes limit the accumulation of short-lived, regulatory proteins within mitochondria, modulate the activity of mitochondrial proteins by protein processing, and mediate the degradation of damaged proteins. Various signaling cascades coordinate the activity of mitoproteases to preserve mitochondrial homeostasis and ensure cell survival. Loss of mitoproteases severely impairs the functional integrity of mitochondria, is associated with aging, and causes pleiotropic diseases. Understanding the dual function of mitoproteases as regulatory and quality control enzymes will help unravel the role of mitochondrial plasticity in aging and disease.
Mitochondria drive apoptosis by releasing pro-apoptotic proteins that promote caspase activation in the cytosol. The rhomboid protease PARL, an intramembrane cleaving peptidase in the inner membrane, ...regulates mitophagy and plays an ill-defined role in apoptosis. Here, we employed PARL-based proteomics to define its substrate spectrum. Our data identified the mitochondrial pro-apoptotic protein Smac (also known as DIABLO) as a PARL substrate. In apoptotic cells, Smac is released into the cytosol and promotes caspase activity by inhibiting inhibitors of apoptosis (IAPs). Intramembrane cleavage of Smac by PARL generates an amino-terminal IAP-binding motif, which is required for its apoptotic activity. Loss of PARL impairs proteolytic maturation of Smac, which fails to bind XIAP. Smac peptidomimetics, downregulation of XIAP or cytosolic expression of cleaved Smac restores apoptosis in PARL-deficient cells. Our results reveal a pro-apoptotic function of PARL and identify PARL-mediated Smac processing and cytochrome c release facilitated by OPA1-dependent cristae remodelling as two independent pro-apoptotic pathways in mitochondria.
Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune ...signalling via the cyclic GMP-AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS-STING-TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS-STING-TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.
Abstract
A female full-term newborn of 41 + 2 weeks gestational age with a respiratory adaptation disorder and hypercapnia was transferred from an external maternity clinic to our pediatric intensive ...care unit. The child is the second child of healthy, non-consanguineous parents. Multiple dysmorphias were noticed at arrival. We identified a choanal atresia/stenosis on both sides in the respiratory tract, a high palate, a submucous cleft palate, a bifid uvula, a laryngeal cleft and a bronchus suis. The child required intubation and ventilation. In addition, we recognized brachydactyly of the hands and feet. The phalanges were not visibly separable. There was nail hypoplasia and rocker bottom feet on both sides. Furthermore, we saw an anal atresia. In routine laboratory work-up, a hypoglycemia and not measurable low TSH serum concentration was noticed. Extended endocrinological laboratory diagnostics revealed a complete pituitary insufficiency. On cranial MRI, a large, iso- to slightly hyperintense space-occupying mass (3.8x3.7x2.5 cm3), originating from the hypothalamus was observed. The brainstem was displaced posteriorly by the mass. The imaging is consistent with a hypothalamic hamartoma. With regard to the present findings, we assumed an underlying genetic cause of the congenital malformations. As a clinical diagnosis, a Pallister-Hall syndrome was suspected. As described in our case, we saw the characteristic features: dysmorphia of the hands and feet, upper respiratory tract, anal atresia, and hypothalamic hamartomas. The Pallister-Hall syndrome is caused by mutations in the GLI3 gene on the 7p13 chromosome. It is inherited in an autosomal dominant manner and its prevalence is unknown. In our patient, a heterozygous, probably pathogenic variant in the GLI3-Gene was proven by Next Generation Sequencing (NGS).
Objective. Upper gastrointestinal (GI) bleeding from esophageal or gastric fundus varices is a common complication of portal hypertension in liver cirrhosis and carries a high mortality rate of ...20-35%. Stratifying high-risk patients for variceal bleeding is mainly based on endoscopic scoring. The purpose of this study was to develop a simple clinical score to assess the bleeding risk. Material and methods. A total of 111 patients with chronic liver diseases were included during evaluation for potential liver transplantation and were followed for 6 years. Findings at study entry were analyzed for their value in predicting hemorrhages. Results. Twenty-four patients (22%) developed upper GI hemorrhages from varices during the follow-up period. Common characteristics at study entry of patients with future bleedings included viral hepatitis or alcoholic etiology, advanced-stage cirrhosis, decreased liver function, impaired hemostasis and endoscopic presence of varices. These parameters were also independent predictors of bleedings. A four-item Bleeding Risk Score, including cholinesterase <2.25 kU/l, international normalized ratio (INR) >1.2, viral or alcoholic etiology and presence of varices, was used to identify patients at high (>2 points) or low (≤2) risk of bleedings, and found superior in sensitivity and specificity to the Child-Pugh or MELD score. Conclusions. A simple clinical score can predict the risk for upper GI bleedings in patients with chronic liver disease. This Bleeding Risk Score may help to supplement current endoscopic and clinical approaches to identify high-risk patients.
: Background/Aims: Alterations of plasma coagulation factor XIII may contribute to bleeding disorders in patients with liver cirrhosis. As standard clotting tests such as prothrombin time or ...activated thromboplastin time (aPTT) cannot detect factor XIII deficiency, this may often be overlooked in clinical practice. We aimed to define factor XIII's clinical and prognostic role in chronic liver disease.
Patients and methods: Factor XIII activities were assessed among various other parameters in 111 patients with chronic liver diseases during evaluation for liver transplantation in a prospective study.
Results: Unlike coagulation factors II, V or VII, factor XIII activity was maintained in the majority of patients with liver cirrhosis. However, although rarely, factor XIII deficiencies (<50%) occurred, especially in Child C cirrhosis. Factor XIII levels correlated with liver's biosynthetic capacity (cholinesterase activity, albumin, total protein) as well as with platelet count, global coagulation tests and other single coagulation factors. Patients reporting a current systemic bleeding tendency at study entry had significantly reduced factor XIII. In a 6‐year follow‐up, patients with factor XIII <50% had a significantly increased risk of severe upper gastrointestinal bleed, and reduced factor XIII (<50%, 50–75% vs. normal) was associated with increased mortality.
Conclusions: Factor XIII deficiency is rare in patients with liver cirrhosis, but is associated with a clinical bleeding tendency and an unfavorable prognosis for future hemorrhages and survival.
Although many advances in antineoplastic therapy have taken place, a clinical breakthrough in the therapy of malignant gliomas is still required. One of the reasons for this is the poor response to ...cytotoxic drugs and irradiation. We established a subline of the rat glioma cell line C6, named C6,5 x 10(-7) Dox, by exposure to increasing doses of doxorubicin for 5 months. C6,5 x 10(-7) Dox cells expressed high levels of P-glycoprotein (Pgp), known to function as an energy-dependent efflux pump for lipophilic drugs causing the multidrug resistance phenotype. Pgp, which normally has a molecular weight of 170 to 180 kd, appears in C6,5 x 10(-7) Dox cells as two bands with a molecular weight of 140 and 120 kd in western blots. In addition to the typical cross-resistance to doxorubicin, daunorubicin, vincristine and etoposide, we observed a significant resistance of the C6,5 x 10(-7) Dox cell line to irradiation, which cannot be explained by Pgp-expression.
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