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.

Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mt-ISR

“…FGF21 and HTRA2 orthologous genes ( fgf21 , htra2 ) were also significantly upregulated in the double chchd10 -/- & chchd2 -/- model (Fig. 7 B) as was the previously described oxygen responsive transcript, cox4i2 (25–27) (Fig. 7 C).…”

“…CHCHD2 and CHCHD10 share 58% sequence identity and have a common ancestor in yeast, suggesting that these proteins might have partially overlapping function (15). In vitro studies have reported that loss of either CHCHD2, CHCHD10 or both, impacts mitochondrial respiration (10, 16), survival/growth following exposure to various cellular stressors (9, 10, 16, 17), the mitochondrial integrated stress response (mt-ISR) (18–22), apoptosis (23, 24), as well as the transcription of the oxygen responsive gene COX4I2 (25–27).…”

Long-noncoding RNA MALAT1 sponges microRNA-92a-3p to inhibit doxorubicin-induced cardiac senescence by targeting ATG4a

“…Exosome Hypoxia also downregulated the expression levels of Mtfp1, a participant in Dox-induced cardiac injury [64]. While, exosome Hypoxia increased the expression levels of Hspa1a (autophagy inducer) [65], Cox4i2 (the modulator of mitochondrial response) [66], and ATP1B2 (cardiac oxidative stress inhibitor) [67], accompanied by cellular rejuvenation. Also, these metabolism-related genes were the target genes of miR-92a-3p to maintain cardiac metabolism homeo-stasis [23].…”

Gain of 20q11.21 in Human Pluripotent Stem Cells Impairs TGF-β-Dependent Neuroectodermal Commitment

“…Next, CHCHD2 was identified as a prime candidate linking Bcl-xL to the transcriptomic changes, because it is consistently downregulated in mutant cells and the protein binds Bcl-xL, resulting in a decreased oligomerization of Bax (Liu et al., 2015). This downregulation may be through a self-regulatory feedback loop, as CHCHD2 is able to translocate to the nucleus to transactivate itself as well as other genes that contain oxygen-responsive element sequences in their promoter region (Aras et al., 2013, Grossman et al., 2017). Another interesting function of CHCHD2 is its capacity to interact with the SMADs (2/3/4) and thus modulate the transcription of TGF-β-mediated target genes (Zhu et al., 2016).…”