Authors: Habiba Elshenawy, Jessica Wu, Neeraja Purandare, Siddhesh Aras
Published: 2025-04-21
DOI: 10.1158/1538-7445.am2025-1385
Source: Full article
Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1, aka CHCHD2) is a bi-organellar regulator protein localized in the mitochondria and the nucleus. In the mitochondria, MNRR1 regulates oxidative phosphorylation (OxPhos) to generate ATP and inhibits intrinsic apoptosis. Nuclear MNRR1 regulates the transcription of ∼ 5000 genes, including many cancer-related genes. Reasonably, this explains the upregulated MNRR1 expression in different cancers. Triple-negative breast Cancer (TNBC) is associated with an aggressive phenotype. The lack of hormonal receptors and tumor heterogeneity cause resistance to conventional therapies and the inability to develop targeted treatments. Using TNBC as a model system, we aim to identify the mechanism of MNNR1 function as an anti-apoptotic protein. Intrinsic apoptosis involves disruption of equilibrium between pro- and anti-apoptotic proteins. Anti-apoptotic proteins are translocated upon apoptotic stimuli by pro-apoptotic proteins that accumulate on the outer mitochondrial membrane (OMM), causing its permeabilization. This allows the release of cytochrome c from mitochondria to cytosol to activate the caspase pathway. Our findings show that MNRR1 resides in two different forms in the mitochondria based on its Y99 phosphorylation (pY99R1). pY99R1 induces OxPhos, while the non-phosphorylated protein (npR1) interacts preferentially with the anti-apoptotic protein Bcl-xL. Induction of MNRR1 inhibition using knockout cells or chemical inhibitors sensitize cells to an apoptotic stimulus. MNRR1 knockout cells display a pro-apoptotic phenotype as observed by Bax oligomerization. Voltage-dependent anion channel (VDAC) is an OMM protein that interacts with Bcl-xL, preventing the release of cytochrome c to the cytosol. Our study shows that npR1 enhances the VDAC-Bcl-xL interaction complex. This anti-apoptotic function is facilitated by N-terminal 52 amino acids constituting the putative Mitochondrial localization Sequence (MLS) in MNRR1 protein. Collectively, the findings of our study highlight the potential use of MNRR1 as a therapeutic target for novel therapeutics or in combination with existing therapies in TNBC.