Supercompetitor status of Drosophila Myc cells requires p53 as a fitness sensor to reprogram metabolism and promote viability.

In growing tissues, cell fitness disparities can provoke interactions that promote stronger cells at the expense of the weaker in a process called cell competition. The mechanistic definition of cell fitness is not understood, nor is it understood how fitness differences are recognized. Drosophila cells with extra Myc activity acquire "supercompetitor" status upon confrontation with wild-type (WT) cells, prompting the latter's elimination via apoptosis.

Disruption of HIF-1α in hepatocytes impairs glucose metabolism in diet-induced obesity mice.

The liver plays a central role in glucose homeostasis in the whole-body by responding to environmental factors including nutrients, hormones, and oxygen. In conditions of metabolic overload such as diabetes mellitus and obesity, coordinated regulation between oxygen supply and consumption has been reported to be disrupted and subsequently cause tissue hypoxia, although pathological significance of the disease-related hypoxia remains elusive. To investigate the role of tissue hypoxia in the liver on systemic glucose homeostasis, mice lacking HIF-1α gene, a critical component of a master regulator of hypoxic response, in hepatocytes were exposed to high fat/sucrose diet (HFSD).

HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice.

Background & Aims: Chronic alcohol intake stimulates hepatic oxygen consumption and subsequently causes liver hypoxia, leading to activation of hypoxia inducible factor-1 (HIF-1). Although HIF-1 plays a crucial role in the metabolic switch from aerobic to anaerobic metabolism in response to hypoxia, its roles in the regulation of lipid metabolism in alcoholic fatty liver remain unknown.

Methods: Wild-type and hepatocyte-specific HIF-1α-null mice were subjected to a 6% ethanol-containing liquid diet for 4 weeks, and functional effects of loss of the HIF-1α gene on lipid metabolism were examined in the liver.

HIF-1alpha is necessary to support gluconeogenesis during liver regeneration.

Coordinated recovery of hepatic glucose metabolism is prerequisite for normal liver regeneration. To examine roles of hypoxia inducible factor-1alpha (HIF-1alpha) for hepatic glucose homeostasis during the reparative process, we inactivated the gene in hepatocytes in vivo. Following partial hepatectomy (PH), recovery of residual liver weight was initially retarded in the mutant mice by down-regulation of hepatocyte proliferation, but occurred comparably between the mutant and control mice at 72h after PH.

Soluble factors mediate competitive and cooperative interactions between cells expressing different levels of Drosophila Myc.

When neighboring cells in the developing Drosophila wing express different levels of the transcription factor, dMyc, competitive interactions can occur. Cells with more dMyc proliferate and ultimately overpopulate the wing, whereas cells with less dMyc die, thereby preventing wing overgrowth. How cells sense dMyc activity differences between themselves and the nature of the process leading to changes in growth and survival during competition remain unknown.

DRONC coordinates cell death and compensatory proliferation.

Accidental cell death often leads to compensatory proliferation. In Drosophila imaginal discs, for example, gamma-irradiation induces extensive cell death, which is rapidly compensated by elevated proliferation. Excessive compensatory proliferation can be artificially induced by "undead cells" that are kept alive by inhibition of effector caspases in the presence of apoptotic stimuli.

Bax-like protein Drob-1 protects neurons from expanded polyglutamine-induced toxicity in Drosophila.

Bcl-2 family proteins regulate cell death through the mitochondrial apoptotic pathway. Here, we show that the Drosophila Bax-like Bcl-2 family protein Drob-1 maintains mitochondrial function to protect cells from neurodegeneration. A pan-neuronal knockdown of Drob-1 results in lower locomotor activity and a shorter lifespan in adult flies.

Effect of oxidative stress on translocation of DAF-16 in oxygen-sensitive mutants, mev-1 and gas-1 of Caenorhabditis elegans.

Mutations in the mev-1 and gas-1 genes of the nematode Caenorhabditis elegans render animals hypersensitive to oxygen and paraquat, and lead to premature aging. We show that both mutants overproduce superoxide anion in isolated sub-mitochondrial particles, which probably explains their hypersensitivity to oxidative stress. The daf-16 gene encodes a fork-head transcription factor that is negatively regulated by an insulin-signaling pathway.

Coenzyme Q10 can prolong C. elegans lifespan by lowering oxidative stress.

The mev-1 gene encodes cytochrome b, a large subunit of the Complex II enzyme succinate-CoQ oxidoreductase. The mev-1(kn1) mutants are hypersensitive to oxidative stress and age precociously, probably because of elevated superoxide anion production in mitochondria. Coenzyme Q (CoQ) is essential for the mitochondrial respiratory chain.

A complex II defect affects mitochondrial structure, leading to ced-3- and ced-4-dependent apoptosis and aging.

The mev-1(kn1) mutation of Caenorhabditis elegans is in Cyt-1, which encodes a subunit of succinate-coenzyme Q oxidoreductase in the mitochondrial electron transport chain. Mutants are hypersensitive to oxidative stress and age precociously in part because of increased superoxide anion production. Here, we show that mev-1 mutants are defective in succinate-coenzyme Q oxidoreductase, possess ultrastructural mitochondrial abnormalities (especially in muscle cells), show a loss of membrane potential, have altered CED-9 and Cyt-1 protein levels under hyperoxia, and contain ced-3-and ced-4-dependent supernumerary apoptotic cells.