From the Cover: Trypanosomal TAC40 constitutes a novel subclass of mitochondrial β-barrel proteins specialized in mitochondrial genome inheritance

Mitochondria cannot form de novo but require mechanisms allowing their inheritance to daughter cells. In contrast to most other eukaryotes Trypanosoma brucei has a single mitochondrion whose single-unit genome is physically connected to the flagellum. Here we identify a β-barrel mitochondrial outer membrane protein, termed tripartite attachment complex 40 (TAC40), that localizes to this connection. TAC40 is essential for mitochondrial DNA inheritance and belongs to the mitochondrial porin protein family. However, it is not specifically related to any of the three subclasses of mitochondrial porins represented by the metabolite transporter voltage-dependent anion channel (VDAC), the protein translocator of the outer membrane 40 (TOM40), or the fungi-specific MDM10, a component of the endoplasmic reticulum–mitochondria encounter structure (ERMES). MDM10 and TAC40 mediate cellular architecture and participate in transmembrane complexes that are essential for mitochondrial DNA inheritance. In yeast MDM10, in the context of the ERMES, is postulated to connect the mitochondrial genomes to actin filaments, whereas in trypanosomes TAC40 mediates the linkage of the mitochondrial DNA to the basal body of the flagellum. However, TAC40 does not colocalize with trypanosomal orthologs of ERMES components and, unlike MDM10, it regulates neither mitochondrial morphology nor the assembly of the protein translocase. TAC40 therefore defines a novel subclass of mitochondrial porins that is distinct from VDAC, TOM40, and MDM10. However, whereas the architecture of the TAC40-containing complex in trypanosomes and the MDM10-containing ERMES in yeast is very different, both are organized around a β-barrel protein of the mitochondrial porin family that mediates a DNA–cytoskeleton linkage that is essential for mitochondrial DNA inheritance.Mitochondria are a hallmark of all eukaroytic cells. They derive from an endosymbiontic event between a free-living bacterium and a presumably prokaryotic host cell. More than 1.5 billion years of evolution resulted in a great diversification of mitochondria. As a consequence, the shape and number of organelles per cell as well as size, content, copy number, and organization of their genomes vary greatly between different taxons (1). However, all eukaryotes must be able to faithfully transmit mitochondria to their offspring (2, 3).Unlike most other eukaryotes, the parasitic protozoa Trypanosoma brucei has a single mitochondrion throughout its life and its cell cycle. Due to the single-unit nature of the mitochondrion, its duplication must be coordinated with the duplication of the nucleus (4). The mitochondrial genome of T. brucei, termed kinetoplast DNA (kDNA), is essential for growth of both the procyclic insect stage and the bloodstream form of the parasite (5). It consists of a disk-shaped single-unit kDNA network that localizes to a distinct region within the mitochondrial matrix (6). The kDNA is physically connected with the cytosolic basal body, the organizing center of the eukaryotic flagellum, via a high-order transmembrane structure termed tripartite attachment complex (TAC) (7) of which only few components have been identified (8–10). Replication of the kDNA network occurs at a defined stage of the cell cycle shortly before the onset of the nuclear S phase. After replication, the kDNA networks need to be correctly positioned so that during cell and mitochondrial division each daughter cell receives a single organelle with a single kDNA network. This process requires an intact TAC and is mediated by the movement of the basal body: one kDNA network remains connected to the basal body of the old flagellum whereas the other one segregates with the basal body of the new flagellum (7, 11).Unlike trypanosomes, Saccharomyces cerevisiae propagates by budding and contains highly dynamic mitochondria that constantly divide and fuse (12, 13). Mitochondrial inheritance in budding yeast therefore requires a mechanism to move mitochondria and their genomes from the mother cell into the growing bud. The protein-associated mitochondrial genomes of S. cerevisiae, termed nucleoids, localize to dozens of globular foci that are distributed all over the organelles. Most actively replicating nucleoids are associated with a protein complex that includes the outer membrane (OM) protein MDM10 as a central unit, as well as the proteins MDM12, MDM34, and MMM1 (14–16). The protein complex forms the endoplasmic reticulum (ER)–mitochondria encounter structure (ERMES) tethering the ER to the mitochondrion (17). The ERMES has also been suggested to connect to cytosolic actin fibers that mediate the movement of mitochondria to the bud of dividing yeast cells (14, 18, 19). Besides its role in mitochondrial inheritance, the ERMES has been implicated in maintenance of mitochondrial morphology and in phospholipid and calcium exchange as well as in the assembly of the protein translocase of the mitochondrial OM (TOM) (20, 21). Some of the proposed ERMES functions are controversial and there is evidence that some of them might be due to secondary effects caused by the drastically altered mitochondrial morphology (22).The central ERMES subunit, the β-barrel protein MDM10 belongs to the mitochondrial porin superfamily, which comprises the three members voltage-dependent anion channel (VDAC), Tom40, and MDM10. Whereas VDAC and Tom40 have so far been found in all eukaryotes, including T. brucei (23, 24), MDM10 is specific to the fungal clade.In this study we identify a mitochondrial OM protein of T. brucei as a novel component of the TAC. We show that the protein defines a novel subclass of the mitochondrial porin superfamily that is specialized in mitochondrial DNA inheritance.     

Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up.

AIMS: Peripheral arterial occlusive disease is associated with a high risk of cardiovascular morbidity and mortality. We prospectively examined the association of the ankle-brachial index (ABI) and arterial plaques in carotid and femoral arteries with incident myocardial infarctions (MIs) and cardiovascular and total mortality in 1325 participants of the population-based MONICA Augsburg Survey 1989/90. METHODS AND RESULTS: At baseline, 6.1% of men and 2.6% of women had an ABI < or =0.9. At least one plaque in the carotid or femoral arteries was identified in 51.8% of men and 36.3% of women. During a 13-year follow-up, 58 persons (4.4%) suffered a MI before age 75 and 189 persons (14.3%) died, 86 (6.5%) of them from cardiovascular causes. Kaplan-Meier curves confirmed both measurements as strong predictors for all three endpoints (P<0.0001). Cox regression analysis revealed an increase of the risk for MI and cardiovascular and total mortality of 22 (P=0.012), 35, and 32% (P<0.00001), respectively, per 0.1 unit decrease in ABI. Correction for measurement error in ABI increased these estimates. The increase in risk for MI and cardiovascular and total mortality was 52, 70, and 45%, respectively, for each increase in the number of plaque-affected arteries (P<0.0001). CONCLUSION: Both ABI and number of plaque-affected arteries are strong predictors for incident MI and cardiovascular and total mortality.     

The effect of risky alcohol use and smoking on suicide risk: findings from the German MONICA/KORA-Augsburg Cohort Study

Background  

Smoking and heavy alcohol use predicts suicidal behaviour. Whether the simultaneous presentation of both conditions induces an amplified effect on risk prediction has not been investigated so far.     

High prevalence of undiagnosed diabetes mellitus in Southern Germany: Target populations for efficient screening. The KORA survey 2000

AIMS/HYPOTHESIS: To estimate the prevalence of undiagnosed diabetes mellitus, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), and their relations with cardiovascular risk factors in the general population aged 55 to 74 years in Southern Germany. METHODS: Oral glucose tolerance tests were carried out in a random sample of 1353 subjects aged 55 to 74 years participating in the KORA (Cooperative Health Research in the Region of Augsburg) Survey 2000. Prevalences of glucose tolerance categories (1999 WHO criteria) were adjusted for sample probabilities. The numbers needed to screen (NNTS) to identify one person with undiagnosed diabetes were estimated from age-adjusted logistic regression models. RESULTS: Sample design-based prevalences of known and unknown diabetes, IGT, and IFG were 9.0%, 9.7%, 16.8%, 9.8% in men, and 7.9%, 6.9%, 16.0%, 4.5% in women, respectively. In both sexes, participants with undiagnosed diabetes had higher BMI, waist circumference, systolic blood pressure, triglycerides, uric acid, and lower HDL-cholesterol than normoglycaemic subjects. A combination of abdominal adiposity, hypertension, and parental diabetes in men resulted in a NNTS of 2.9 (95%CI: 2.0-4.6). In women, the combination of increased triglycerides, hypertension and parental diabetes history yielded a NNTS of 3.2 (95%CI: 2.2-5.1). CONCLUSION/INTERPRETATION: About 40% of the population aged 55 to 74 years in the Augsburg region have disturbed glucose tolerance or diabetes. Half of the total cases with diabetes are undiagnosed. Cardiovascular risk factors worsen among glucose tolerance categories, indicating the need for screening and prevention. Screening for undiagnosed diabetes could be most efficient in individuals with abdominal adiposity (men), hypertriglyceridaemia (women), hypertension, and parental diabetes history.     

Long-term survival in patients with different combinations of evidence-based medications after incident acute myocardial infarction: results from the MONICA/KORA Myocardial Infarction Registry

Background

Use of the four evidence-based medications [EBMs: antiplatelet agent, beta-blocker, statin and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB)] after acute myocardial infarction (AMI) has a clear impact on 1-year survival. Aim of this study was to evaluate the association between different EBM combinations at discharge and long-term survival after AMI.

Methods

From a German population-based AMI registry, 2,886 men and 958 women were included, aged 28–74 years, hospitalized with an incident AMI between 2000 and 2008. All data were collected by standardized interviews and chart review. All-cause mortality was assessed for all registered persons in 2010. Median follow-up time was 6.0 years (interquartile range 4.1 years). Survival analyses and multivariate Cox regression analysis were conducted.

Results

Of the 3,844 patients, 70.3 % were prescribed all four EBMs; 23.8 % received three, 4.6 % two, and 1.3 % were discharged with one or no EBM. Long-term survival was 71.7 % [95 % confidence interval (CI) 55.4–82.9 %], 64.7 % (95 % CI 59.2–69.6 %) and 60.2 % (95 % CI 51.9–67.5 %) in patients with four, three and <3 EBMs, respectively. Patients prescribed three or less EBMs without ACEI/ARB showed similar long-term survival to those receiving four EBMs. In Cox regression analysis after adjustment for confounding variables, the hazard ratio for long-term mortality in patients with four EBMs versus three or less EBMs was 0.63 (95 % CI 0.53–0.74).

Conclusions

Prescribing of a combination of all four EBMs appeared to improve clinical outcomes in AMI patients by significantly reducing long-term mortality. Hospital discharge is a critical time for optimal long-term management.     

Prognostic value of apolipoprotein B and A-I in the prediction of myocardial infarction in middle-aged men and women: results from the MONICA/KORA Augsburg cohort study.

AIMS: To investigate the association between apolipoprotein B (apoB), A-I (apoA-I), the apoB/apoA-I ratio, and the incidence of coronary events. METHODS AND RESULTS: Analysis included 1414 men and 1436 women aged 35-64 years without a prior coronary event who participated in the population-based MONICA Augsburg survey 1984-85 (median followed-up period 13 years). Incidence of fatal and non-fatal myocardial infarction, and sudden cardiac death was assessed using data of the MONICA/KORA Augsburg coronary event registry. During follow-up, 114 incident coronary events occurred in men and 31 in women. In multivariable analysis, an increase of 1 standard deviation in the serum concentration of apoB was associated with an increased risk of coronary events in men [hazard ratio (HR)=1.49; 95% confidence interval (CI); 1.25-1.78] and in women (HR=1.73; 95% CI; 1.32-2.27). By contrast, elevated concentrations of apoA-I were not associated with a significantly decreased risk of coronary events in either sex (HR=0.91). Furthermore, the predictive power of the apoB/apoA-I ratio was similar to that of the total cholesterol/HDL cholesterol ratio in men and women. CONCLUSION: ApoB and the apoB/apoA-I ratio were strong predictors of coronary events in middle-aged men and women, whereas apoA-I did not add significantly to the estimation of future coronary risk.