12 research outputs found

    Threading Granules in Freiburg : 2nd International Symposium on "One Mitochondrion, Many Diseases – Biological and Molecular Perspectives", a FRIAS Junior Researcher Conference, Freiburg im Breisgau, Germany, March 9th/10th, 2016

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    Altered mitochondrial activities play an important role in many different human disorders, including cancer and neurodegeneration. At the Freiburg Institute of Advanced Studies (FRIAS) Junior Researcher Conference “One Mitochondrion, Many Diseases – Biological and Molecular Perspectives” (University of Freiburg, Freiburg, Germany), junior and experienced researches discussed common and distinct mechanisms of mitochondrial contributions to various human disorders

    Central role of mic10 in the mitochondrial contact site and cristae organizing system

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    The mitochondrial contact site and cristae organizing system (MICOS) is a conserved multi-subunit complex crucial for maintaining the characteristic architecture of mitochondria. Studies with deletion mutants identified Mic10 and Mic60 as core subunits of MICOS. Mic60 has been studied in detail; however, topogenesis and function of Mic10 are unknown. We report that targeting of Mic10 to the mitochondrial inner membrane requires a positively charged internal loop, but no cleavable presequence. Both transmembrane segments of Mic10 carry a characteristic four-glycine motif, which has been found in the ring-forming rotor subunit of F1Fo-ATP synthases. Overexpression of Mic10 profoundly alters the architecture of the inner membrane independently of other MICOS components. The four-glycine motifs are dispensable for interaction of Mic10 with other MICOS subunits but are crucial for the formation of large Mic10 oligomers. Our studies identify a unique role of Mic10 oligomers in promoting the formation of inner membrane crista junctions

    Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

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    Mitofilin proteins are crucial organizers of mitochondrial architecture. They are located in the inner mitochondrial membrane and interact with several protein complexes of the outer membrane, thereby generating contact sites between the two membrane systems of mitochondria. Within the inner membrane, mitofilins are part of hetero-oligomeric protein complexes that have been termed the mitochondrial inner membrane organizing system (MINOS). MINOS integrity is required for the maintenance of the characteristic morphology of the inner mitochondrial membrane, with an inner boundary region closely apposed to the outer membrane and cristae membranes, which form large tubular invaginations that protrude into the mitochondrial matrix and harbor the enzyme complexes of the oxidative phosphorylation machinery. MINOS deficiency comes along with a loss of crista junction structures and the detachment of cristae from the inner boundary membrane. MINOS has been conserved in evolution from unicellular eukaryotes to humans, where alterations of MINOS subunits are associated with multiple pathological conditions.

    The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation

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    The pro-apoptotic Bcl-2 protein Bax can permeabilize the outer mitochondrial membrane and therefore commit human cells to apoptosis. Bax is regulated by constant translocation to the mitochondria and retrotranslocation back into the cytosol. Bax retrotranslocation depends on pro-survival Bcl-2 proteins and stabilizes inactive Bax. Here we show that Bax retrotranslocation shuttles membrane-associated and membrane-integral Bax from isolated mitochondria. We further discover the mitochondrial porin voltage-dependent anion channel 2 (VDAC2) as essential component and platform for Bax retrotranslocation. VDAC2 ensures mitochondria-specific membrane association of Bax and in the absence of VDAC2 Bax localizes towards other cell compartments. Bax retrotranslocation is also regulated by nucleotides and calcium ions, suggesting a potential role of the transport of these ions through VDAC2 in Bax retrotranslocation. Together, our results reveal the unanticipated bifunctional role of VDAC2 to target Bax specifically to the mitochondria and ensure Bax inhibition by retrotranslocation into the cytosol

    The MINOS complex: Keeper of mitochondrial membrane architecture

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    Mitochondria are surrounded by two distinct membranes. While the outer membrane confines the organelle, the inner membrane has a key role in cellular energy metabolism. The inner mitochondrial membrane is subdivided into the inner boundary membrane, which is closely opposed to the outer membrane, and large irregular invagi- nations termed cristae. Narrow tubular openings – the crista junctions – connect cristae membrane and inner boundary membrane domains. Additionally, sites of contact between inner boundary and outer mitochondrial membranes are frequently observed. We have recently discovered a mitochondrial inner membrane organizing system (MINOS complex) that is crucial for both, the formation of crista junctions and membrane contact sites. MINOS is composed of six inner membrane proteins: the two highly conserved core subunits Fcj1/mitofilin and Mio10/MINOS1 together with Aim5, Aim13, Aim37 and Mio27. Deletion of FCJ1 or MIO10 in yeast abolishes MINOS formation and leads to a grossly altered mitochondrial ultrastructure with extended stacks of sheet-like cristae membranes and the loss of crista junctions. Moreover, MINOS interacts with several protein complexes of the outer mitochondrial membrane, like the SAM/TOB complex or the TOM complex at membrane contact sites. Formation of MINOS con- tact sites supports the import of precursor proteins from the cytosol into the intermembrane space and outer membrane. A detailed structure/function analysis of Fcj1/mitofilin revealed that membrane tethering, MINOS integrity and formation of crista junctions depend on different Fcj1/mitofilin protein domains

    Healthcare seeking behaviours among immigrants in Sweden

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    Bakgrund: HÀlsan i sig och möjligheten att söka vÄrd vid nedsatt hÀlsa ingÄr i samhÀllets folkhÀlsoansvar. Det ansvaret omfattar Àven de migranter som finns i Sverige. Hur ohÀlsa tas omhand inom sjukvÄrden och hur hÀlsoutvecklingen kan stödjas bland migranter har betydelse för hela samhÀllet och samhÀllsekonomin. Syfte: Att ta reda pÄ mönstret för migranter nÀr det gÀller att söka vÄrd, vad man söker för, vilka hinder som kan finnas för vÄrdsökande, bÄde bland migranterna sjÀlva och i vÄrdapparaten och hur dessa problem kan överbryggas. Metod: Detta Àr en litteraturbaserad studie. De metoder och den design som anvÀndes för att analysera och granska studierna baseras pÄ STROBE och Malteruds granskningsmal för litteraturer studier samt GRADE för metodstyrkan. Resultat: I den systematiska sökningen identifierades 15 artiklar som uppfyllde sökkriterierna. Dessa anvÀndes för att svara pÄ frÄgorna om vÄrdsökandet och utgjorde underlag för vÀrderingen av den vetenskapliga styrkan nÀr det gÀller fynden relaterade till vÄrdsökandet. Orsaker till vÄrdsökande omfattade bÄde infektionssjukdomar och icke smittsamma sjukdomar, bland dessa psykisk ohÀlsa. Det vÄrdsökande beteendet Àr bland annat knutet till kulturella uppfattningen om sjukdomars orsaker men ocksÄ till sprÄkproblem. SjukvÄrdens organisation och personalens attityder utgör ocksÄ hinder för ett adekvat vÄrdsökande bland migranter. Slutsats: VÄrdsökande beteende hos immigranter i Sverige varierar beroende pÄ bakgrund och etnicitet gÀllande olika sjukdomar och religiös tro. De mönster som pÄverkar vÄrdsökande beteendet Àr dock desamma hos alla grupper och styrs av kulturella och socioekonomiska faktorer liksom av litteracitet och sprÄkbarriÀrer.Background: Healthcare seeking behaviours among immigrants in Sweden is a public health issue since the health outcome not only affects immigrants but also the Swedish population, the healthcare system and impacts on the national economy. In order to alleviate the problems and support the development of health among immigrants we need a thorough picture of the situation today. Objectives: To explore the healthcare seeking behaviours of immigrants in Sweden looking at the different epidemiological reasons and challenges faced during healthcare seeking and the support than can be appropriate for combating the challenges. Method: Literature based study. The methods and designs applied in the articles were assessed and graded on method strength by STROBE, Malterud guidelines and GRADE respectively. Result: 15 articles were identified through a systematic search and used to determine the quality and strength of the scientific methods used to explore the questions of the study. Reasons for seeking health care were signs and symptoms, communicable as well as non-communicable diseases, among those mental health issues. Obstacles to seeking health care were cultural background as well as perception of causes of diseases and language barriers; in addition, the organisation of care and the attitudes among providers were also seen as obstacles to seeking healthcare. Conclusion: Health seeking behaviour among immigrants vary according to ethnic backgrounds as pertains to diseases and beliefs. However, the challenges faced are common among the different groups and they range from cultural social economic to health illiteracy and language barriers

    Role of mitochondrial inner membrane organizing system in protein biogenesis of the mitochondrial outer membrane

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    Mitochondria contain two membranes, the outer membrane and the inner membrane with folded cristae. The mitochondrial inner membrane organizing system (MINOS) is a large protein complex required for maintaining inner membrane architecture. MINOS interacts with both preprotein transport machineries of the outer membrane, the translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM). It is unknown, however, whether MINOS plays a role in the biogenesis of outer membrane proteins. We have dissected the interaction of MINOS with TOM and SAM and report that MINOS binds to both translocases independently. MINOS binds to the SAM complex via the conserved polypeptide transport–associated domain of Sam50. Mitochondria lacking mitofilin, the large core subunit of MINOS, are impaired in the biogenesis of ÎČ-barrel proteins of the outer membrane, whereas mutant mitochondria lacking any of the other five MINOS subunits import ÎČ-barrel proteins in a manner similar to wild-type mitochondria. We show that mitofilin is required at an early stage of ÎČ-barrel biogenesis that includes the initial translocation through the TOM complex. We conclude that MINOS interacts with TOM and SAM independently and that the core subunit mitofilin is involved in biogenesis of outer membrane ÎČ-barrel proteins.

    Dual Role of Mitofilin in Mitochondrial Membrane Organization and Protein Biogenesis

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    The mitochondrial inner membrane consists of two domains, inner boundary membrane and cristae membrane that are connected by crista junctions. Mitofilin/Fcj1 was reported to be involved in formation of crista junctions, however, different views exist on its function and possible partner proteins. We report that mitofilin plays a dual role. Mitofilin is part of a large inner membrane complex, and we identify five partner proteins as constituents of the mitochondrial inner membrane organizing system (MINOS) that is required for keeping cristae membranes connected to the inner boundary membrane. Additionally, mitofilin is coupled to the outer membrane and promotes protein import via the mitochondrial intermembrane space assembly pathway. Our findings indicate that mitofilin is a central component of MINOS and functions as a multifunctional regulator of mitochondrial architecture and protein biogenesis.
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