Access Type

Open Access Dissertation

Date of Award

January 2018

Degree Type


Degree Name



Molecular Biology and Genetics

First Advisor

Lawrence I. Grossman


CHCHD10 (Coiled-coil Helix Coiled-coil Helix Domain containing protein 10) and MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1, also known as CHCHD2), have been shown by us to be stress regulators of mitochondrial function that act both in the mitochondria and in the nucleus. Both are members of the twin CX9C family, but CHCHD10 in particular, has been found in mutant form to be linked to a myriad of neurodegenerative conditions. In mitochondria, both activate cytochrome c oxidase (COX) whereas in the nucleus, both act as transcription regulators of a subset of genes that contain a 13-bp sequence termed as the oxygen responsive element (ORE). We previously modeled events at the ORE to consist of a complex of RBPJk with either the transcriptional repressor CXXC5 or the transcriptional activator MNRR1. We show that CHCHD10 co-purifies with COX and up-regulates its activity by serving as a scaffolding protein required for MNRR1 phosphorylation, mediated by ARG (ABL2 kinase). Surprisingly, in the nucleus CHCHD10 protein down-regulates the expression of ORE-harboring genes by interacting with and augmenting the activity of CXXC5. The CHCHD10 gene is maximally transcribed in cultured cells at 8% oxygen, unlike MNRR1, which is maximally expressed at 4%, suggesting a fine-tuned oxygen-sensing system that adapts to the varying oxygen concentrations in the human body. We also show that cells predominantly harboring two CHCHD10 disease mutants (G66V and P80L) are defective for cellular oxidative phosphorylation, have lower membrane potential and higher reactive oxygen species (ROS) levels as compared to WT-CHCHD10. The mutant proteins are also defective in the nucleus as they fail to interact with CXXC5 and repress transcription at the ORE. Taken together, these effects point to a putative cellular mitochondrial defect as well dysregulation of transcription of ORE-harboring gene leading to the neurodegenerative phenotype observed in patients. We discuss these findings to generate a generalized model for cellular responses to moderate levels of hypoxia and a possible mechanism for the observed phenotype in patients with mutations in this gene.