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Undergraduate Research Project Management System

Mitochondrial function and histone H2A

Status Current
Seeking Researchers No
Start Date 09/01/2008
End Date 06/30/2009
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Last Updated 07/05/2008 01:25AM


  Jocelyn Krebs

Student Researchers
  Jason Bell


The long-term objective of this research is to understand how cells respond to numerous stresses and DNA damaging agents, such as the damage caused by reactive oxygen species (ROS). We wish to understand how stress responses are regulated and coordinated at the level of chromatin structure, and particularly how chromatin structure impacts the communication between the nucleus and mitochondria. Defects in mitochondrial function can result in impaired energy production, defects in nitrogen, heme and fatty acid metabolism, and overproduction of ROS. In humans mitochondrial defects are implicated in multiple diseases, such as neuromuscular diseases resulting from reduced ATP production and type II diabetes, linked to misregulation of glucose and fatty acid metabolism. The increased ROS produced by dysfunctional mitochondria is associated with neurodegenerative processes in Alzheimer's and Parkinson's diseases, and plays central roles in carcinogenesis and aging. The integrity and function of mitochondria is inextricably linked to nuclear functions, since the vast majority of mitochondrial proteins are encoded by nuclear genes, as are the components of pathways that regulate quality control and turnover of mitochondria (such as the ‘self-eating' process of autophagy). All nuclear gene expression is regulated by chromatin, which comprises DNA wrapped around octamers of histone proteins (2 each of H2A, H2B, H3 and H4) to form nucleosomes. Using the yeast Saccharomyces cerevisiae as a model organism, we have identified a single point mutation in histone H2A (S122A) that results in a profound destabilization of mitochondria. We have previously shown that this H2A residue, which is phosphorylated in response to damage, has a universal role in surviving multiple insults and may provide a nexus for coordinating stress-response pathways. We are performing experiments to uncover the mechanism by which this essential chromatin component results in rapid loss of mitochondrial DNA.

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