Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity.

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.

Mitochondrial Proteases: Multifaceted Regulators of Mitochondrial Plasticity.

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.

PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis.

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.

A simple clinical score predicts high risk for upper gastrointestinal hemorrhages from varices in patients with chronic liver disease.

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 (

Clinical and prognostic role of plasma coagulation factor XIII activity for bleeding disorders and 6-year survival in patients with chronic liver disease.

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.