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Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation. Dysfunctions of the mitochondrial OXPHOS system lead to severe human disorders. Here, the authors analyzed a mouse mutant that mimics a mitochondrial disorder patient and find that reactive oxygen species trigger RNA release and inflammatory pathway in liver. [ABSTRACT FROM AUTHOR]

Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease‐specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid‐driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell‐derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V. Treatment of mutant cells with AMPK activator reestablishes fatty acid‐driven OXPHOS and protects mice against cardiac dysfunction. Synopsis: Defective cardiolipin remodeling due to mutation in tafazzin, causes Barth syndrome (BTHS) with cardiac impairment and reduced oxidative phosphorylation. Dysfunctional FAO‐driven OXPHOS due to altered AMPK signaling is restored in BTHS models by treatment with AMPK activator. The characteristic pathology observed in Barth syndrome patients is mirrored by TAZG197V mice, which are characterized by severe cardiac dysfunction and reduced oxidative phosphorylation.A switch in the metabolic pathways from oxidative phosphorylation to glycolysis for compensating ATP production is evident in TAZG197V mutants.Due to metabolic shift and increased ATP, AMPK pathway is shut down affecting transcription of CPTs with reduced fatty acid oxidation, a known consequence of heart failure.Functional restoration of cardiac function in TAZG197V mice is reestablished by treating mutant mice with an AMPK activator, which restores fatty acid‐driven oxidative phosphorylation in the heart. [ABSTRACT FROM AUTHOR]

Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2−/− mice using CRISPR/Cas9-mediated genome editing. Rnaset2−/− mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8+ effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The Rnaset2−/− mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies. Studies on interferon-driven brain pathology have so far been hampered by the lack of appropriate animal models. Here the authors characterize RNASET2-deficient mice and show that neuroinflammation and brain atrophy are IFNAR1-dependent. [ABSTRACT FROM AUTHOR]

The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome. Mitochondrial protein import is mediated by the translocase of the outer membrane (TOM), through which nearly all precursors traverse. Here, the authors perform global in vitro kinome profiling and by this identify that DYRK1A phosphorylates TOM70 and promotes import. [ABSTRACT FROM AUTHOR]

This document is a statement of peer review for the Computer Sciences & Mathematics Forum. The volume editors of the proceedings certify that all papers published in this volume have undergone a double-blind peer review process conducted by expert referees. A total of 21 submissions were sent for review, and 8 submissions were accepted to be presented at the 2nd AAAI Workshop on Artificial Intelligence with Biased or Scarce Data (AIBSD). Out of the 8 accepted submissions, 5 were encouraged to further submit to MDPI for publication. The acceptance rate for the AIBSD workshop was approximately 38%, and the acceptance rate for MDPI submission was approximately 24%. Each paper received an average of two reviews, and a total of 18 reviewers were involved in the process. The review process ensured high quality by assigning an average of 2-3 papers to each reviewer. The authors declare no conflicts of interest. [Extracted from the article]

Abstract: The yeast protein Taz1 is the orthologue of human Tafazzin, a phospholipid acyltransferase involved in cardiolipin (CL) remodeling via a monolyso CL (MLCL) intermediate. Mutations in Tafazzin lead to Barth syndrome (BTHS), a metabolic and neuromuscular disorder that primarily affects the heart, muscles, and immune system. Similar to observations in fibroblasts and platelets from patients with BTHS or from animal models, abolishing yeast Taz1 results in decreased total CL amounts, increased levels of MLCL, and mitochondrial dysfunction. However, the biochemical mechanisms underlying the mitochondrial dysfunction in BTHS remain unclear. To better understand the pathomechanism of BTHS, we searched for multi-copy suppressors of the taz1Δ growth defect in yeast cells. We identified the branched-chain amino acid transaminases (BCATs) Bat1 and Bat2 as such suppressors. Similarly, overexpression of the mitochondrial isoform BCAT2 in mammalian cells lacking TAZ improves their growth. Elevated levels of Bat1 or Bat2 did not restore the reduced membrane potential, altered stability of respiratory complexes, or the defective accumulation of MLCL species in yeast taz1Δ cells. Importantly, supplying yeast or mammalian cells lacking TAZ1 with certain amino acids restored their growth behavior. Hence, our findings suggest that the metabolism of amino acids has an important and disease-relevant role in cells lacking Taz1 function.Key messages: Bat1 and Bat2 are multi-copy suppressors of retarded growth of taz1Δ yeast cells.Overexpression of Bat1/2 in taz1Δ cells does not rescue known mitochondrial defects.Supplementation of amino acids enhances growth of cells lacking Taz1 or Tafazzin.Altered metabolism of amino acids might be involved in the pathomechanism of BTSH. [ABSTRACT FROM AUTHOR]

Lower eukaryotes like the kinetoplastid parasites are good models to study evolution of cellular pathways during steps to eukaryogenesis. In this study, a kinetoplastid parasite, Leishmania donovani, was used to understand the process of mitochondrial translocation of a nucleus-encoded mitochondrial protein, the mitochondrial tryparedoxin peroxidase (mTXNPx).We report the presence of an N-terminal cleavable mitochondrial targeting signal (MTS) validated through deletion and grafting experiments. We also establish a novel finding of calmodulin (CaM) binding to the MTS of mTXNPx through specific residues. Mutation of CaM binding residues, keeping intact the residues involved in mitochondrial targeting and biochemical inhibition of CaM activity both in vitro and in vivo, prevented mitochondrial translocation. Through reconstituted import assays, we demonstrate obstruction of mitochondrial translocation either in the absence of CaM or Ca2+ or in the presence of CaM inhibitors. We also demonstrate the prevention of temperature-driven mTXNPx aggregation in the presence of CaM. These findings establish the idea that CaM is required for the transport of the protein to mitochondria through maintenance of translocation competence posttranslation. [ABSTRACT FROM AUTHOR]

Lower eukaryotes like the kinetoplastid parasites are good models to study evolution of cellular pathways during steps to eukaryogenesis. In this study, a kinetoplastid parasite, Leishmania donovani, was used to understand the process of mitochondrial translocation of a nucleus-encoded mitochondrial protein, the mitochondrial tryparedoxin peroxidase (mTXNPx). We report the presence of an N-terminal cleavable mitochondrial targeting signal (MTS) validated through deletion and grafting experiments. We also establish a novel finding of calmodulin (CaM) binding to the MTS of mTXNPx through specific residues. Mutation of CaM binding residues, keeping intact the residues involved in mitochondrial targeting and biochemical inhibition of CaM activity both in vitro and in vivo, prevented mitochondrial translocation. Through reconstituted import assays, we demonstrate obstruction of mitochondrial translocation either in the absence of CaM or Ca2+ or in the presence of CaM inhibitors. We also demonstrate the prevention of temperature-driven mTXNPx aggregation in the presence of CaM. These findings establish the idea that CaM is required for the transport of the protein to mitochondria through maintenance of translocation competence posttranslation. [ABSTRACT FROM AUTHOR]

Summary Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs, integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin remodeling, upon loss of the cardiolipin acyl transferase tafazzin, decreases HIF-1α signaling in hypoxia. Tafazzin deficiency does not affect posttranslational HIF-1α regulation but rather HIF-1α gene expression, a dysfunction recapitulated in iPSC-derived cardiomyocytes from Barth syndrome patients with tafazzin deficiency. RNA-seq analyses confirmed drastically altered signaling in tafazzin mutant cells. In hypoxia, tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-κB activation and concomitantly HIF-1α gene expression. Tafazzin-deficient mice hearts display reduced HIF-1α levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin remodeling dampens HIF-1α signaling due to a lack of NF-κB activation through reduced mitochondrial ROS production, decreasing HIF-1α transcription. Graphical Abstract Highlights • Defective remodeling of mitochondrial cardiolipin dampens HIF-1α signaling • ROS-mediated NF-κB activation is impaired in cardiolipin-deficient cells • Defective NF-κB-mediated HIF-1α gene induction decreases the cellular response to hypoxia • Deregulated cardiac response to pressure overload in Barth syndrome mouse Defective remodeling of the mitochondrial phospholipid cardiolipin causes cardiomyopathy in Barth syndrome patients. Chowdhury et al. show that dysfunctional mitochondria affect the HIF-1α response to hypoxia. They demonstrate that mitochondrial ROS is required for NF-κB-mediated gene induction of HIF-1α. [ABSTRACT FROM AUTHOR]