Simultaneous impairment of mitochondrial fission and fusion reduces mitophagy and shortens replicative lifespan.

Aging of biological systems is accompanied by degeneration of mitochondrial functions. Different pathways are active to counteract the processes which lead to mitochondrial dysfunction. Mitochondrial dynamics, the fission and fusion of mitochondria, is one of these quality control pathways. Mitophagy, the controlled degradation of mitochondria, is another one. Here we show that these pathways are linked. A double deletion mutant of Saccharomyces cerevisiae in which two essential components of the fission and fusion machinery, Dnm1 and Mgm1, are simultaneously ablated, contain wild-type like filamentous mitochondria, but are characterized by impaired respiration, an increased sensitivity to different stressors, increased mitochondrial protein carbonylation, and a decrease in mitophagy and replicative lifespan. These data show that a balanced mitochondrial dynamics and not a filamentous mitochondrial morphotype per se is the key for a long lifespan and demonstrate a cross-talk between two different mitochondrial quality control pathways.

The role of mitochondria in fungal aging.

Time-dependent impairments of mitochondrial function play a key role in biological aging. Work on fungal aging models has been instrumental in unraveling basic mechanisms leading to mitochondrial dysfunction and the identification of different pathways active in keeping mitochondria 'healthy' over time. Pathways including those involved in reactive oxygen scavenging, repair of damage, proteostasis, mitochondrial dynamics, and biogenesis, are interconnected and part of a complex quality control system. The individual components of this network are limited in capacity. However, if the capacity of one pathway is overwhelmed, another one may be activated. The mechanisms controlling the underlying cross-talk are poorly understood and subject of intensive investigation.

Mitochondrial quality control: impact on aging and life span - a mini-review.

A fundamental impact of mitochondria on biological aging has been suggested decades ago. One prominent theory explains aging as the result of the age-related accumulation of random molecular damage of biomolecules resulting from the reaction of reactive oxygen species, the majority of which are generated in mitochondria. Although this concept appeared to be very attractive and strongly influenced aging research, in recent years more and more data accumulated which seem to contradict this theory. However, since these data are derived from reductionist approaches and do not integrate the various components and pathways which are affected as a result of a primary experimental intervention, they are prone to misinterpretation and have to be taken with some caution. Here, after a general introduction of mitochondrial function, we discuss the relevance of various pathways which are involved in keeping mitochondria functional over time. Moreover, we provide examples which emphasize the importance of a critical interpretation of experimental data and the necessity for a holistic analysis of the aging process. The success of such a systems biology approach is strongly dependent on the development of methods for data mining and an efficient analysis and modeling of the huge data sets that are raised.

Fully automated right ventricular volumetry from ECG-gated coronary CT angiography data: evaluation of prototype software.

Enlargement and dysfunction of the right ventricle (RV) is a sign and outcome predictor of many cardiopulmonary diseases. Due to the complex geometry of the RV exact volumetry is cumbersome and time-consuming. We evaluated the performance of prototype software for fully automated RV segmentation and volumetry from cardiac CT data. In 50 retrospectively ECG-gated coronary CT angiography scans the endsystolic (RVVmin) and enddiastolic (RVVmax) volume of the right ventricle was calculated fully automatically by prototype software. Manual slice segmentation by two independent radiologists served as the reference standard. Measurement periods were compared for both methods. RV volumes calculated with the software were in strong agreement with the results from manual slice segmentation (Bland-Altman r = 0.95-0.98; p < 0.001; Lin's correlation Rho = 0.87-0.96, p < 0.001) for RVVmax and RVVmin with excellent interobserver agreement between both radiologists (r = 0.97; p < 0.001). The measurement period was significantly shorter with the software (153 ± 9 s) than with manual slice segmentation (658 ± 211 s). The prototype software demonstrated very good performance in comparison to the reference standard. It promises robust RV volume results and minimizes postprocessing time.

A framework for personalization of coronary flow computations during rest and hyperemia.

We introduce a Computational Fluid Dynamics (CFD) based method for performing patient-specific coronary hemodynamic computations under two conditions: at rest and during drug-induced hyperemia. The proposed method is based on a novel estimation procedure for determining the boundary conditions from non-invasively acquired patient data at rest. A multi-variable feedback control framework ensures that the computed mean arterial pressure and the flow distribution matches the estimated values for an individual patient during the rest state. The boundary conditions at hyperemia are derived from the respective rest-state values via a transfer function that models the vasodilation phenomenon. Simulations are performed on a coronary tree where a 65% diameter stenosis is introduced in the left anterior descending (LAD) artery, with the boundary conditions estimated using the proposed method. The results demonstrate that the estimation of the hyperemic resistances is crucial in order to obtain accurate values for pressure and flow rates. Results from an exhaustive sensitivity analysis have been presented for analyzing the variability of trans-stenotic pressure drop and Fractional Flow Reserve (FFR) values with respect to various measurements and assumptions.

Detection, grading and classification of coronary stenoses in computed tomography angiography.

Recently conducted clinical studies prove the utility of Coronary Computed Tomography Angiography (CCTA) as a viable alternative to invasive angiography for the detection of Coronary Artery Disease (CAD). This has lead to the development of several algorithms for automatic detection and grading of coronary stenoses. However, most of these methods focus on detecting calcified plaques only. A few methods that can also detect and grade non-calcified plaques require substantial user involvement. In this paper, we propose a fast and fully automatic system that is capable of detecting, grading and classifying coronary stenoses in CCTA caused by all types of plaques. We propose a four-step approach including a learning-based centerline verification step and a lumen cross-section estimation step using random regression forests. We show state-of-the-art performance of our method in experiments conducted on a set of 229 CCTA volumes. With an average processing time of 1.8 seconds per case after centerline extraction, our method is significantly faster than competing approaches.

PaCATB, a secreted catalase protecting Podospora anserina against exogenous oxidative stress.

A differential mass spectrometry analysis of secreted proteins from juvenile and senescent Podospora anserina cultures revealed age-related differences in protein profiles. Among other proteins with decreased abundance in the secretome of senescent cultures a catalase, termed PaCATB, was identified. Genetic modulation of the abundance of PaCATB identified differential effects on the phenotype of the corresponding strains. Deletion of PaCatB resulted in decreased resistance, over-expression in increased resistance against hydrogen peroxide. While the lifespan of the genetically modified strains was found to be unaffected under standard growth conditions, increased exogenous hydrogen peroxide stress in the growth medium markedly reduced the lifespan of the PaCatB deletion strain but extended the lifespan of PaCatB over-expressors. Overall our data identify a component of the secretome of P. anserina as a new effective factor to cope with environmental stress, stress that under natural conditions is constantly applied on organisms and influences aging processes.