To broadly explore mitochondrial structure and function as well as the communication of mitochondria with other cellular pathways, we constructed a quantitative, high-density genetic interaction map (the MITO-MAP) in Saccharomyces cerevisiae. The MITO-MAP provides a comprehensive view of mitochondrial function including insights into the activity of uncharacterized mitochondrial proteins and th...

The generation of a proton gradient across the inner mitochondrial membrane (IMM) is an essential energy conservation event that couples the oxidation of carbohydrates and fat to the synthesis of ATP. Studies in isolated mitochondria have established that the chemical gradient for protons (pH m) and the mitochondrial membrane potential ( m) contribute independently to the proton-motive force...

DNA repair capacity of eukaryotic cells has been studied extensively in recent years. Mammalian cells have been engineered to overexpress recombinant nuclear DNA repair proteins from ectopic genes to assess the impact of increased DNA repair capacity on genome stability. This approach has been used in this study to specifically target O(6)-methylguanine DNA methyltransferase (MGMT) to the mitoc...

Cisplatin is a potent chemotherapeutic agent that is used to treat many human malignancies. Unfortunately, in addition to side effects such as ototoxicity, anaphylaxis, and bone marrow suppression, a significant percentage of patients receiving cisplatin develop severe nephrotoxicity. Mitochondrial dysfunction that is mediated via the generation of reactive oxygen species has been implicated in...

Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders, characterized by resting tremor, rigidity, bradykinesia, and postural instability. These symptoms are associated with massive loss of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) causing an estimated 70-80% depletion of dopamine (DA) in the striatum, where their projections are loca...

Much current work in artificial intelligence focuses on computer programs that aid scientists with complex reasoning tasks. Recent work has indicated that one key to the creatior~:..@f intelligent systems is the incorporation of large amounts of task-specific knowledge. Building knowledge-based, or expert, systems from scratch can be very time-consuming, however. This suggests the need for gene...

Computational models of a large metabolic system can be assembled from modules that represent a biological function emerging from interaction of a small subset of molecules. A "skeleton model" is tested here for a module that regulates the first phase of dynamic adaptation of oxidative phosphorylation (OxPhos) to demand in heart muscle cells. The model contains only diffusion, mitochondrial out...

The behavior of Dempster's rule of combination in typical situations is examined. Particularly, it is shown that assessing a zero value or a very small value may lead to very different results. Moreover a comparison with a possibility theory-based approach in case of conf l ict ing information is provided. The general problem of representing uncertainty with one or several numbers is addressed....

Mitochondrial DNA (mtDNA) mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia) due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ car...