Abstract

Specific Aim 1. Mechanism of mitochondrially-triggered cell death. We have recently demonstrated that permeabilized mitochondria release apoptotic factors. providing a testable biochemical, molecular and cellular hypothesis for the mitochondrial regulation of cell death. Firstly, we will test the predictions of our model for cell death by measuring the ability of death-inducers to both induce release of apoptotic factors from mitochondria, and the ability of mitochondrial regulators to inhibit such release. Secondly, our hypothesis for the order of events in cell death will be tested with purified microsomes, mitochondria, and nuclei, and combinations thereof. Thirdly in whole cells, we will observe the sequence of pathological events in toxin- induced apoptosis, and measure the time course and efficacy of mitochondrial effectors to apoptosis.
Specific Aim 2. Investigation of the cause-and-effect relationships between mitochondrial antioxidant and repair enzymes and age-related mitochondrial DNA mutagenesis. Using the quantitative assay of mutagenesis developed in the first grant period, we will investigate the effect of specific enzymes to protect cells and animals from mtDNA mutagenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG011967-07
Application #
2732548
Study Section
Special Emphasis Panel (ZRG1-NLS-1 (02))
Program Officer
Finkelstein, David B
Project Start
1993-05-15
Project End
2000-06-30
Budget Start
1998-07-15
Budget End
1999-06-30
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618

  Publications

Shan, Yuxi; Cortopassi, Gino (2016) Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. Mitochondrion 26:94-103
Schoenfeld, Robert; Wong, Alice; Silva, Jillian et al. (2010) Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation. Mitochondrion 10:143-50
Rolo, Anabela P; Palmeira, Carlos M; Cortopassi, Gino A (2009) Biosensor plates detect mitochondrial physiological regulators and mutations in vivo. Anal Biochem 385:176-8
Lu, Chunye; Schoenfeld, Robert; Shan, Yuxi et al. (2009) Frataxin deficiency induces Schwann cell inflammation and death. Biochim Biophys Acta 1792:1052-61
Silva, Jillian M; Wong, Alice; Carelli, Valerio et al. (2009) Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia. Neurobiol Dis 34:357-65
Napoli, Eleonora; Morin, Dexter; Bernhardt, Rita et al. (2007) Hemin rescues adrenodoxin, heme a and cytochrome oxidase activity in frataxin-deficient oligodendroglioma cells. Biochim Biophys Acta 1772:773-80
Prigione, Alessandro; Cortopassi, Gino (2007) Mitochondrial DNA deletions induce the adenosine monophosphate-activated protein kinase energy stress pathway and result in decreased secretion of some proteins. Aging Cell 6:619-30
Alemi, Mansour; Prigione, Alessandro; Wong, Alice et al. (2007) Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript. Free Radic Biol Med 42:32-43
Lu, Chunye; Cortopassi, Gino (2007) Frataxin knockdown causes loss of cytoplasmic iron-sulfur cluster functions, redox alterations and induction of heme transcripts. Arch Biochem Biophys 457:111-22
Shan, Yuxi; Napoli, Eleonora; Cortopassi, Gino (2007) Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet 16:929-41

Showing the most recent 10 out of 35 publications