MNRR1, a Biorganellar Regulator of Mitochondria

Abstract

The central role of energy metabolism in cellular activities is becoming widely recognized. However, there are many gaps in our knowledge of the mechanisms by which mitochondria evaluate their status and call upon the nucleus to make adjustments. Recently, a protein family consisting of twin CX₉C proteins has been shown to play a role in human pathophysiology. We focus here on two family members, the isoforms CHCHD2 (renamed MNRR1) and CHCHD10. The better studied isoform, MNRR1, has the unusual property of functioning in both the mitochondria and the nucleus and of having a different function in each. In the mitochondria, it functions by binding to cytochrome c oxidase (COX), which stimulates respiration. Its binding to COX is promoted by tyrosine-99 phosphorylation, carried out by ABL2 kinase (ARG). In the nucleus, MNRR1 binds to a novel promoter element in COX4I2 and itself, increasing transcription at 4% oxygen. We discuss mutations in both MNRR1 and CHCHD10 found in a number of chronic, mostly neurodegenerative, diseases. Finally, we propose a model of a graded response to hypoxic and oxidative stresses, mediated under different oxygen tensions by CHCHD10, MNRR1, and HIF1, which operate at intermediate and very low oxygen concentrations, respectively.

Figure 1

Alignment of human CHCHD10, human MNRR1, and yeast Mix17. Identical residues (^∗) and similar residues (.) are indicated.

Figure 2

Model for transcriptional response to decreasing oxygen levels. The model proposes that, as tissue oxygen levels decrease from the artificial 20% level typically used for tissue culture, different transcriptional programs come into play to try to achieve homeostasis.

Figure 3

Model for MNRR1 function. The model shows the known functions of MNRR1 in both the nucleus and the mitochondria. Whether CHCHD10 functions similarly remains to be determined.