The long-term objective of this project is to contribute to the understanding of mitochondrial biogenesis in eukaryotic cells using the baker's yeast (Saccharomyces cerevisiae) as the model organism. The overall goal of the present proposal is to characterize novel molecular mechanisms that stabilize the mitochondrial genome, which codes for seven members of the electron transport chain (ETC) in S. cerevisiae. Failure to synthesize any of the members of the ETC will lead to a non-respiratory phenotype and more importantly, to the irreversible loss of mitochondrial DNA (mtDNA). Therefore any mechanism that even indirectly impairs mitochondrial translation will lead to mitochondrial dysfunction. Our preliminary studies indicate that the null mutant of YGR150C (ygr150c) inherits (mtDNA) but experiences a very rapid, thorough and irreversible loss of the mitochondrial genome, even in the presence of non-fermentable carbon sources. This phenotype is shared by null mutants of genes that are directly involved in the maintenance of the mitochondrial genome. YGR150C gene product (Ygr150cp) has pentatricopeptide (PPR) motifs, which have been shown to be required for translation of specific mitochondrial-encoded mRNAs, both in yeast and humans. Based on these observations, we hypothesize that YGR150C is either directly involved in the maintenance of mtDNA or alternatively is essential for mitochondrial transcription or translation of at least one member of the ETC. Consequently mtDNA copy number highly depends on Ygr150cp cellular levels. We will test this hypothesis by assessing how Ygr150cp cellular levels affect mitochondrial transcription, processing and/or stability of mitochondrial transcripts. We will also determine the effect of Ygr150cp on the rate of mitochondrial translation, DNA replication, and mtDNA copy number. Loss of mitochondrial genome is the molecular hallmark of the mitochondrial depletion syndromes (MDS), a heterogeneous group of serious and usually fatal developmental diseases that are prevalent in the pediatric population referred for neurological evaluation. Only a minority of the cases can be explained by current genetic testing. We anticipate that data obtained by achieving the proposed aims will lead to a better understanding of mitochondrial gene expression and eventually explain how mitochondrial dysfunction contributes to human disease. Public Health Relevance: Relevance of this research to public health Loss of mitochondrial genome is the molecular hallmark of the mitochondrial depletion syndromes (MDS), a heterogeneous group of serious and usually fatal developmental diseases that are prevalent in the pediatric population referred for neurological evaluation. Only a minority of the cases can be explained by current genetic testing. We anticipate that data obtained by achieving the proposed aims will lead to a better understanding of mitochondrial gene expression and eventually explain how mitochondrial dysfunction contributes to human disease.

Public Health Relevance

Relevance of this research to public health Loss of mitochondrial genome is the molecular hallmark of the mitochondrial depletion syndromes (MDS), a heterogeneous group of serious and usually fatal developmental diseases that are prevalent in the pediatric population referred for neurological evaluation. Only a minority of the cases can be explained by current genetic testing. We anticipate that data obtained by achieving the proposed aims will lead to a better understanding of mitochondrial gene expression and eventually explain how mitochondrial dysfunction contributes to human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM087169-04
Application #
8323280
Study Section
Special Emphasis Panel (ZGM1-MBRS-0 (GC))
Program Officer
Krasnewich, Donna M
Project Start
2009-09-05
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$90,520
Indirect Cost
$16,270
Name
Alcorn State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
075084897
City
Alcorn State
State
MS
Country
United States
Zip Code
39096