Fis1 deficiency selects for compensatory mutations responsible for cell death and growth control defects.

Genetic mutations affecting mitochondrial fission and fusion proteins cause human neurological disorders, but are assumed to be well tolerated in yeast. The conserved mitochondrial fission protein Dnm1/Drp1 is required for normal mitochondrial division, but also promotes cell death in mammals and yeast. Fis1, an outer mitochondrial membrane-anchored receptor for Dnm1/Drp1, also can promote cell death in mammals, but appears to have prosurvival activity in yeast. Here we report that deletion of the FIS1 gene in yeast consistently results in acquisition of a secondary mutation that confers sensitivity to cell death. In several independently derived FIS1 knockouts, tiling arrays and genomic sequencing identified the secondary mutation as a premature termination in the same stress-response gene, WHI2. The WHI2 mutation rescues the mitochondrial respiratory defect (petite formation) caused by FIS1 deficiency, but also causes a failure to suppress cell growth during amino-acid deprivation. Thus, loss of Fis1 drives the selection for specific compensatory mutations that confer defective growth control and cell death regulation, characteristic of human tumor cells. The important long-term survival function of Fis1 that is compensated by WHI2 mutation appears to be independent of fission factor Dnm1/Drp1 and its adaptor Mdv1, but may be mediated through a second adaptor Caf4, as WHI2 is also mutated in a CAF4 knockout.

Respiratory and hemodynamic effects of methadone in pregnant women.

Minute ventilation, end-tidal PCO2, O2 and CO2 concentrations in expired air, pulse rate and arterial blood pressure were measured in the last half of pregnancy in eight women taking methadone daily. Measurements were made with the subjects seated at rest, during the steady state of 50-watt bicycle exercise, and during recovery. Calculations of O2 consumption. CO2 production, alveolar ventilation and oxygen debt were made. Studies were repeated in five subjects postpartum. Methadone diminishes the normal hyperventilation of pregnancy and its effect persists for more than 24 h. When comparisons are made of pregnant and postpartum values, some respiratory stimulation during pregnancy is apparent. Maternal oxygen debt following standard exercise during pregnancy is diminished after the daily dose of methadone and the maternal heart rate response to exercise is diminished concurrently. The maternal hypoventilation induced by methadone and maintained during exercise may be relevant to the low birth weights and high incidence of sudden infant death syndrome observed by others in the offspring of methadone-dependent women.