A novel, non-canonical mechanism for the nuclear entry of large mitochondrial enzymes

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To achieve efficiency, the interior of a cell is well-compartmentalized. Mitochondria are organelles in the cell where a number of specialized proteins work toward the production of energy to fuel all cellular functions. The nucleus is another organelle within the cell where the genes are located. Because of the critical importance of the genes, the interior of the nucleus is well protected with specialized membranes that surround the nucleus. Entry and exit from the nucleus occur only through specialized channels called nuclear pores (NP), that only allow proteins below a size limit to entry. In addition, a protein originating from another part of the cell, has to have a specific segment in one of its two ends, called "nuclear localization sequence" (NLS), to which specific traffic chaperones can bind it and guide it through the NP into the nucleus. We recently found that a very important enzyme only thought to exist within the mitochondria, was unexpectedly found in the nucleus as well. This enzyme (called pyruvate dehydrogenase complex, PDC) was functional in the nucleus, producing a critical metabolite for gene regulation. But PDC is the largest enzyme known in biology (its size far exceeds the size limit of NPs) and has no NLS. Thus it remains a mystery how PDC can enter the nucleus and its presence there suggests that an unknown, novel mechanism may exist for the entrance of large proteins in the nucleus. This research program aims to discover this novel entry mechanism. We will pursue early evidence from our preliminary experiments, that mitochondria travel and make contact points with the nucleus. A protein called Mitofusin2 (MFN2) that is found in both the mitochondria and the nucleus membranes, is used to tether the 2 organelles together. This allows the PDC to enter the external nuclear membrane and interact with one of the main proteins of the internal nuclear membrane, i.e. lamin, enabling its nuclear entry. We believe that this is a feature of all cells in the body and thus we will study many different cell types using advance molecular and imaging techniques, including super-resolution confocal microscopy. Our work is expected to significantly enhance the relative recent and incompletely understood concept of communication of mitochondria with the nucleus and, in general, the communication pathways between different cellular organelles. Its potential implications are many and range from the function of cells during embryo development, to the function of cells during metabolic stress, to the mechanism of aging. This research program provides excellent opportunities of the training of graduate students and is expected to result in important publications that cross many different aspects of biology.