Mitochondrial quality control and biogenesis 

Mitochondrial quality control

Mitophagy is the degradation of damaged or excessive mitochondria through the autophagy pathway. This process is thought to serve a quality control purpose by ensuring that only highly functional mitochondria are maintained in the cell. In some inherited forms of Parkinson's disease (PD), molecules that function in mitophagy (Pink1 and Parkin) are disrupted. This observation has led to the model that these cases of PD are caused by a failure of mitochondrial quality control, leading to the accumulation of dysfunctional mitochondria. We are studying the role of PD-related genes and mitochondrial dynamics genes in mitophagy.

Assembling the oxidative phosphorylation machinery

There are challenges to the assembly of large, multi-subset protein complexes. The most interesting challenge is that the production of the various subunits must be coordinated, because excess subunits that cannot assemble are often not stable. This challenge applies to the oxidative phosphorylation machinery, which is composed of five multi-subunit complexes. However, the assembly of these complexes is additionally complex. For Complexes I, III, IV, and V, some subunits are encoded by the mtDNA, whereas others are encoded by the nuclear DNA. They are the only protein complexes with a dual genetic origin, and therefore, gene expression from the two genomes must be coordinated. We are using genetics screens and biochemical studies to discover the pathways that ensure proper stoichiometry of the subunits. 

Folding of proteins in the mitochondrial matrix

Proteins that reside in the mitochondrial matrix—the compartment enclosed by the mitochondrial inner membrane—take a complicated journey to their final destination. The precursor is synthesized in the cytoplasm by cytosolic ribosomes and is kept in an unfolded state by chaperones. It is then escorted to the mitochondrial surface, where it is threaded, in an unfolded state, through a translocase in the outer membrane and another translocase in the inner membrane. Upon entering the mitochondrial matrix, its mitochondrial targeting signal is removed by the matrix processing peptidase. At this point, the mature protein must fold into its native structure. We have identified a pathway that facilitates the folding of some matrix proteins and are using biochemical studies to understand its molecular mechanism of action.