Welcome to our website, and thank you for your interest in our research! We are accepting applications for a post-doctoral position. Please send your CV to Neal if interested. Graduate students interested in rotating in the lab should also contact Neal via email.
The goal of the laboratory is to explore basic mechanisms of mitochondrial biology and their relevance to human health and disease. The mitochondrion serves as the powerhouse of the cell. The mitochondrion appears genetically simple, with a small matrilineally inherited genome, however many basic mechanisms in the expression of mitochondrial genetic information (transcription, DNA maintenance) are incompletely understood.
Studies of Mitochondrial Transcription
The mitochondrial genome is densely packed with genes, all of which are required for electron transport and the generation of ATP by the mitochondrion. The mitochondrial DNA is transcribed in two directions, but the two transcripts are not equivalent. We are addressing several questions in the laboratory related to mitochondrial transcription:
- What is the role of the nuclear-encoded LRPPRC in mitochondrial transcription? Evidence has shown that this gene, which is mutated in a form of pediatric mitochondrial disease, may be important in maintaining full transcriptional potency.
- How many primary transcripts can be produced from the mitochondrial genome under normal circumstances?
- How is mitochondrial transcription impaired in various forms of mitochondrial disease?
Failures in many of the steps between the coding of mitochondrial genes in the mitochondrial DNA and the assembly of these proteins into the electron transport complexes can lead to disease. Mechanisms exclusively due to transcriptional failure have not been convincingly shown, but the example of LRPPRC suggests the possibility that transcription is important in disease.
Mitochondrial heteroplasmy refers to the presence of more than one distinct mitochondrial genomic sequences in an individual or tissue. Mitochondrial heteroplasmy is clinically important because mutations that interfere with mitochondrial function cause progressively more severe features as the level of the mutation (relative to the normal sequence) rises. There are two ways to become heteroplasmic, you can be born heteroplasmic, due to mutations that are usually present in your mother, or you can develop heteroplasmy due to mutation. In the lab we are looking at several questions related to heteroplasmy.
- How does heteroplasmy develop as we age? Is age-related heteroplasmy important in age-related neurodegenerative disorders?
- How does heteroplasmy get established in pluripotent stem cells?
The lab is supported by grants from the National Institutes of Health and the Philadelphia Foundation and by The Children’s Hospital of Philadelphia.