The overall objectives of the proposed research are to understand the breadth and the mechanisms of a novel signaling pathway from mitochodria t the nucleus called retrograde regulation, whereby nuclear gene expression changes in response to alterations in the functional state of mitochondria. Th retrograde response pathway is known to require three genes, RTG1,RTG2, and RTG3. The following specific aims are proposed: 1) search for new targets of the RTG genes, and search for new retrograde responsive genes using promoter trap and RT-PCR screens; 2) analyze mechanisms of a transcriptional switch in which the RTG genes function as mitochondrial stress response genes in that they are recruited to the expression of some genes encoding mitochdrial proteins, primarily in cells with reduced or compromised mitochondrial activities; 3) test the details of a general model for control of the retrograde response pathway, which posits that the low abundance basic helix-loop-helix/leucine zipper (bHLH/Zip) transcription factor, Rtg3p, is sequestered in an inactive form by an inhibitor, which it is proposed is encoded by a fourth gene in the pathway, RTG4, in cells with fully functional mitochondria. In cells with dysfunctional mitochondria, the putative molecular chaperone activity of Rtg2 is effectively increased, releasing the sequestered Rtg3p to make it available to heterodimerize with the higher abundant bHLH/Zip transcription factor, Rtg1p, for transcriptional activation; and 4) to determine the role of the retrograde pathway in the 'artificial' apoptotic response in yeast involving Bax and Bcl2. Recent findings have revealed an intriguing relationship between mitochondrial function and programmed cell death (apoptosis) in multi-cellular organisms. Apoptosis is a process that plays an important role in development, tissue homeostasis and oncogenesis. There is now clear evidence that dysfunctional mitochondria can initiate a cascade of events leading to apoptosis involving the pro-apoptotic membrane pore forming protein, Bax, and its antagonist Bcl-2. When expressed in yeast, Bax has been reported to kill respiratory competent rho+ cells but only causes a growth arrest of respiratory incompetent rho o petites. Overall, these studies should provide new insights into how cells respond to changes in the functional state of mitochondria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37GM022525-23
Application #
2605255
Study Section
Biochemistry Study Section (BIO)
Project Start
1979-05-01
Project End
2003-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
23
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Kucej, Martin; Kucejova, Blanka; Subramanian, Ramiah et al. (2008) Mitochondrial nucleoids undergo remodeling in response to metabolic cues. J Cell Sci 121:1861-8
Liu, Zhengchang; Thornton, Janet; Spirek, Mario et al. (2008) Activation of the SPS amino acid-sensing pathway in Saccharomyces cerevisiae correlates with the phosphorylation state of a sensor component, Ptr3. Mol Cell Biol 28:551-63
Kucej, Martin; Butow, Ronald A (2007) Evolutionary tinkering with mitochondrial nucleoids. Trends Cell Biol 17:586-92
Liu, Zhengchang; Butow, Ronald A (2006) Mitochondrial retrograde signaling. Annu Rev Genet 40:159-85
Giannattasio, Sergio; Liu, Zhengchang; Thornton, Janet et al. (2005) Retrograde response to mitochondrial dysfunction is separable from TOR1/2 regulation of retrograde gene expression. J Biol Chem 280:42528-35
Chen, Xin Jie; Wang, Xiaowen; Kaufman, Brett A et al. (2005) Aconitase couples metabolic regulation to mitochondrial DNA maintenance. Science 307:714-7
Ferreira Junior, Jose Ribamar; Spirek, Mario; Liu, Zhengchang et al. (2005) Interaction between Rtg2p and Mks1p in the regulation of the RTG pathway of Saccharomyces cerevisiae. Gene 354:2-8
Liu, Zhengchang; Spirek, Mario; Thornton, Janet et al. (2005) A novel degron-mediated degradation of the RTG pathway regulator, Mks1p, by SCFGrr1. Mol Biol Cell 16:4893-904
Butow, Ronald A; Avadhani, Narayan G (2004) Mitochondrial signaling: the retrograde response. Mol Cell 14:1-15
Liu, Zhengchang; Sekito, Takayuki; Spirek, Mario et al. (2003) Retrograde signaling is regulated by the dynamic interaction between Rtg2p and Mks1p. Mol Cell 12:401-11

Showing the most recent 10 out of 31 publications