(523e) Posttranslational Modifications As Regulators of Activity in Nucleus Versus Mitochondria

MNRR1 (also called CHCHD2) functions in a retrograde response pathway between nucleus and mitochondria. It is present in both compartments but has a different function in each compartment and is regulated in each compartment by a different posttranslational modification. It functions to regulate mitochondrial respiration and, upon sensing stress, promotes transcription of genes whose proteins can restore homeostasis. In mitochondria it activates respiration by binding to cytochrome c oxidase (COX), the terminal complex of the electron transport chain. In order to bind with high affinity, MNRR1 must be phosphorylated within mitochondria on tyrosine at position 99, which is carried out by Abl2 kinase (also called ARG). The binding site of MNRR1 on COX than can be modeled by an energy minimization approach places it near the docking site for cytochrome c, which transfers electrons from complex III to COX such that Tyr-99 phosphorylation could alter the docking site geometry and thus reaction kinetics. This modeling is supported by preliminary data on altered reaction kinetics. In the nucleus, MNRR1 functions as a transcription activator, binding to a conserved element present in the promoters of genes whose transcription is stimulated by hypoxia and other oxidative stress. Transactivation is regulated by acetylation at Lys-119, which inhibits transcription, whereas deacetylation by SIRT1 or substitution of a non-acetylatable residue at that position, activates it. Thus, compartment-specific posttranslational events act to modulate this pathway of stress regulation response.