(228co) Gene Regulation and Signal Integration Across Organelles: CX9c Isoform Proteins As Bi-Organellar Transducers Between Mitochondria and the Nucleus

The regulation of gene expression is a crucial component in responding adaptively to stressors that disrupt cellular homeostasis. The regulation of energy metabolism is particularly urgent when a cell is faced with a life-threatening emergency and calls into play multiple gene regulatory systems. A special and interesting case is integration of gene regulatory systems across organelles in a process by which mitochondria signal to the nucleus, called retrograde regulation. We have uncovered two such regulators, members of the CX₉C family of proteins that are typically found in both the nucleus and the mitochondrial intermembrane space. These are MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1, also called CHCHD2) and CHCHD10. The importance of these regulators is emphasized by their being found associated with a number of peripheral neuropathies such as ALS, Parkinsons Disease, and frontotemporal dementia. In the mitochondria both are physically bound to, and co-purify with, cytochrome c oxidase (COX), the terminal protein of the electron transport chain, as well as bound to each other. MNRR1 requires Tyr-99 phosphorylation, carried out in vivo by Abl2 kinase (ARG), for efficient binding to COX. Lack of MNRR1 produces mitochondrial dysfunction, including reduced oxygen consumption, increased free radical production, and mitochondrial fragmentation. However, both proteins are also present in the nucleus, where they serve as modulators of transcription. MNRR1 is maximally produced at 4% oxygen and activates a novel oxygen responsive element (ORE) in the promoter for a COX subunit gene, COX4I2. Similar OREs are present in the promoters of a number of genes that are stress responsive such as SOD, MFN1, PGC-1α, Sirt1, Atg7, and Hsp60; all respond to a change in MNRR1 levels. Fundamental mitochondrial processes such as oxygen consumption, ROS production, growth rate, and mitochondrial shape are regulated by MNRR1 levels. An MNRR1 isoform, CHCHD10 is also present in both the mitochondria and the nucleus. It is maximally induced at 8% oxygen and in the mitochondria it also binds to COX and also causes increased oxygen consumption. However, in the nucleus it functions oppositely at the ORE by repressing transcription. We propose that these proteins provide a gradual cellular systems response to decreasing oxygen concentrations prior to the very low concentrations that trigger a response by the well-known hypoxia inducible factor (HIF).