Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease.

Stress and developmental regulation of the yeast C-type cyclin Ume3p (Srb11p/Ssn8p) complex (Feaver et al., 1994). In addition, a more distantly Katrina F.Cooper, Michael J.Mallory, related cyclin (Pho80p) complexes with the Pho85p Cdk

Meiosis is the developmental program by which diploid organisms produce haploid gametes capable of sexual reproduction. Here we describe the yeast gene AMA1, a new member of the Cdc20 protein family that regulates the multisubunit ubiquitin ligase termed the anaphase promoting complex͞cyclosome (APC͞C). AMA1 is developmentally regulated in that its transcription and splicing occur only in meiotic cells. The meiosis-specific processing of AMA1 mRNA depends on the previously described MER1 splicing factor. Several results indicate that Ama1p is required for APC͞C function during meiosis. First, coimmunoprecipitation assays indicate that Ama1p associates with the APC͞C in vivo. Second, Ama1p is required for the degradation of the B-type cyclin Clb1p, an APC͞C substrate in both meiotic and mitotic cells. Third, ectopic overexpression of AMA1 is able to stimulate ubiquitination of Clb1p in vitro and degradation of Clb1p in vivo. Mutants lacking AMA1 revealed that it is required for the first meiotic division but not the mitotic-like meiosis II. In addition, ama1 mutants are defective for both spore wall assembly and the expression of late meiotic genes. In conclusion, this study indicates that Ama1p directs a meiotic APC͞C that functions solely outside mitotic cell division. The requirement of Ama1p only for meiosis I and spore morphogenesis suggests a function for APC͞C Ama1 specifically adapted to germ cell development. G ametogenesis requires the execution of several interrelated events including genetic exchange, haploidization, and cellular differentiation. Haploidization is achieved through two consecutive nuclear divisions, meiosis I (reductional) and meiosis II (equational). During the reductional division, replicated sister chromatids stay attached and segregate as a single unit to the same pole. The second meiotic division resembles mitosis in that the centromeres of replicated sisters bind to spindles emanating from opposite poles and separate at anaphase II. Finally, during gametogenesis, differentiation programs instruct the formation of specialized cells that are capable of sexual reproduction. In yeast, the haploid products are encapsulated in spores, which have the capacity to mate after they germinate and reenter the mitotic cell cycle (1).Several studies have indicated that the basic mitotic cell cycle machinery is required for many aspects of meiosis (reviewed in ref.2). For example, the budding yeast mitotic cell cycle is driven by the cyclin-dependent protein kinase Cdc28p (3). Cdc28p is activated by a conserved family of proteins termed cyclins (4) with the four B-type cyclins (Clb1-4p) regulating the G 2 ͞M transition. Similarly, the normal execution of meiosis I and II also requires the Cdc28p-Clb1p and Cdc28p-Clb4p kinases (5-7). However, the production of haploid products during meiosis requires two events that are strictly prohibited by mitotic checkpoint pathways (8). First, replicated sister chromatids stay paired during meiosis I rather than segregate to the opposite poles as they do in ...

SUMMARY Mitochondrial morphology is maintained by the opposing activities of dynamin-based fission and fusion machines. In response to stress, this balance is dramatically shifted toward fission. This study reveals that the yeast transcriptional repressor cyclin C is both necessary and sufficient for stress-induced hyper-fission. In response to oxidative stress, cyclin C translocates from the nucleus to the cytoplasm where it is destroyed. Prior to its destruction, cyclin C both genetically and physically interacts with Mdv1p, an adaptor that links the GTPase Dnm1p to the mitochondrial receptor Fis1p. Cyclin C is required for stress-induced Mdv1p mitochondrial recruitment and the efficient formation of functional Dnm1p filaments. Finally, co-immunoprecipitation studies and fluorescence microscopy revealed an elevated association between Mdv1p and Dnm1p in stressed cells that is dependent on cyclin C. This study provides a mechanism by which stress-induced gene induction and mitochondrial fission are coordinated through translocation of cyclin C.

SummaryThe yeast cyclin-C-Cdk8p kinase complex represses the transcription of a subset of genes involved in the stress response. To relieve this repression, cyclin C is destroyed in cells exposed to H 2 O 2 by the 26S proteasome. This report identifies Not4p as the ubiquitin ligase mediating H 2 O 2 -induced cyclin C destruction. Not4p is required for H 2 O 2 -induced cyclin C destruction in vivo and polyubiquitylates cyclin C in vitro by utilizing Lys48, a ubiquitin linkage associated with directing substrates to the 26S proteasome. Before its degradation, cyclin C, but not Cdk8p, translocates from the nucleus to the cytoplasm. This translocation requires both the cell-wallintegrity MAPK module and phospholipase C, and these signaling pathways are also required for cyclin C destruction. In addition, blocking cytoplasmic translocation slows the mRNA induction kinetics of two stress response genes repressed by cyclin C. Finally, a cyclin C derivative restricted to the cytoplasm is still subject to Not4p-dependent destruction, indicating that the degradation signal does not occur in the nucleus. These results identify a stress-induced proteolytic pathway regulating cyclin C that requires nuclear to cytoplasmic relocalization and Not4p-mediated ubiquitylation.