Assembling the components and circuitry for mitochondrial biogenesis

Mammalian mitochondria consist of an estimated 1200 nuclear gene products whose expression and assembly have to be coordinated in space and in time. At present, the protein composition of these organelles is not fully known, and we lack a detailed understanding of the regulatory programs needed to assemble state-specific mitochondria. Our laboratory is using an integrated genomics approach to tackle these problems and applying the insights gained to understanding human disease.

First, we are using a combination of high performance tandem mass spectrometry, large-scale green fluorescent protein tagging and microscopy, and machine learning to construct a protein atlas of mammalian mitochondria. Our atlas consists of an expanded inventory of mitochondrial proteins and their expression levels across a battery of tissues. Through computational genomics, we are able to predict the function of many of these newly identified genes, some of which emerge as candidate disease genes for inborn errors of metabolism.

Second, we are using comparative sequence analysis and microarray profiling to systematically characterize the transcriptional regulatory circuits required for context-dependent regulation of mitochondria. Our methods identify both cis-acting elements enriched upstream of mitochondrial genes and their trans-acting regulators. We are also extending these methods to understand maladaptive responses of the organelle in human diseases.

These efforts represent steps towards our long-term goal of building predictive models of mitochondrial assembly and function that can be used to understand its basic physiology. If successful, we will be able to use these models to develop new therapeutic strategies for both rare and common human diseases that stem from mitochondrial dysfunction.