Biology subjects

Pasupathi, V.

Publications and source records attributed to Pasupathi, V..

3 recordsLinked to original sources

bioRxiv2026

MNRR1 is required for Triple Negative Breast Cancer growth and metastasis and can be targeted by repurposed drugs.

Despite progress in recent decades, breast cancers remain the most diagnosed malignancies, and second leading cause of cancer death, in women. Although improved screening and systemic and endocrine adjuvant approaches have contributed to major declines in breast cancer mortality, current standard of care drugs are extremely toxic, and many women continue to be overtreated. Although nearly two-thirds of breast cancers are hormone-responsive, aggressive subtypes, particularly Triple Negative Breast Cancer (TNBC), still lack safe oral medications. Recently the roles that mitochondria play in TNBC carcinogenesis, metastasis, and resistance to treatment have garnered a great deal of attention. Contrary to the popular dogma that cancer cells are powered by glycolysis, metastatic breast cancer cells have enhanced mitochondrial function. Our work identified that Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22), a key coordinator of mitochondrial-nuclear crosstalk that is physically present in both compartments, is overexpressed in TNBC cells and is an important regulator of metastasis signaling. We have identified Heat Shock Factor 1 (HSF1) as the main transcription factor that activates the MNRR1 promoter in TNBC cell lines. In the mitochondria, MNRR1 protein facilitates ATP production and inhibits apoptosis, whereas in the nucleus it regulates the transcription of stress-responsive genes including several required for epithelial to mesenchymal transition (EMT), metabolic flexibility, and cell growth. Thus, each of the bi-organellar functions of MNRR1 constitutes processes regarded as hallmarks of cancer. For reasons that are not yet fully understood, MNRR1 levels display a significant and robust ancestry bias, showing increased expression in tumor samples from Non-Hispanic Black (NHB) women when compared to disease-matched tumors from Non-Hispanic White (NHW) patients. It is possible that increased levels of MNRR1 may underlie the aggressive metastatic phenotype observed in many NHB patients. In further support of this observation, loss of MNRR1 function, either genetically or by use of inhibitors, reduces TNBC growth and metastasis. MNRR1 therefore is an attractive therapeutic target that could be exploited for design of novel therapies or as adjuncts to existing ones.

cancer biology↗

bioRxiv2025

Transcriptional activation by MNRR1 is effected by recruiting p300 and can be induced by minimal peptides

Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22, AAG10), which functions in both the mitochondria and the nucleus, modulates mitochondrial function as well as cellular stress response. We have previously shown that stress response is predominantly mediated by its nuclear function as a transcriptional regulator; it operates at a conserved 8-bp DNA element that responds to moderate hypoxia, that we have termed the oxygen responsive element (ORE). This 8-bp element is the consensus DNA binding site for the transcription factor Recombination Signal Binding Protein For Immunoglobulin Kappa J Region (RBPJ{kappa}). We previously addressed the mechanism of nuclear MNRR1 by showing that it displaces the inhibitory transcriptional regulator CXXC-type zinc finger protein 5 (CXXC5), facilitating activation of genes harboring the ORE, and that it most effectively does so after deacetylation by SIRT1 at Lys119. A deacetyl mimetic mutant (K-R) rescues the phenotype in both genetic and environmental inflammatory models of defective mitochondrial function. Here we have refined the mechanism by which MNRR1 regulates transcription at the ORE. We show that MNRR1 interacts with RBPJ{kappa} and recruits the transcriptional co-activator p300 to facilitate transcription. We also show that a minimal domain of MNRR1 is sufficient to activate its nuclear function. Peptides based on this minimal domain can activate transcription by MNRR1 by enhancing p300 and RBPJ{kappa} interaction. MNRR1 peptides activate downstream pathways such as mitochondrial biogenesis and the unfolded protein response (UPRmt) in an in vitro model for MELAS.

cell biology↗

bioRxiv2024

Pseudohypoxia-stabilized HIF2α transcriptionally inhibits MNRR1, a druggable target in MELAS

AbstractThe observation that amounts of the mitochondrial regulator MNRR1 (CHCHD2, AAG10, PARK22) are reduced in several pathologies, and that restoration of its level normalizes the pathological phenotype, prompted a search for compounds that could increase MNRR1 levels. High throughput screening of a 2400-compound drug and natural products library uncovered the antifungal drug nitazoxanide and its metabolite tizoxanide as effective enhancers of MNRR1 transcription. Using the mitochondrial disease MELAS (in which various mixtures, called heteroplasmy, of wild-type and mutant mitochondrial DNA (mtDNA) coexist) as a test, we showed that treating a cybrid MELAS model with tizoxanide could restore cellular respiration, enhance mitophagy, and, importantly, shift heteroplasmy toward more wild-type mtDNA. Furthermore, in MELAS patient fibroblasts, the compound could improve mitochondrial biogenesis, enhance autophagy, and protect the fibroblasts from LPS-induced inflammation. Chemical activation of MNRR1 is thus a potential strategy to improve mitochondrial deficits seen in MELAS. Investigation of the mechanism by which MNRR1 is reduced identified that two factors compete to regulate transcription at the MNRR1 promoter - RBPJ{kappa}, which stimulates it, and HIF2, which inhibits it. In MELAS cells there is a pseudohypoxic state that stabilizes HIF2, leading to transcriptional inhibition of MNRR1. Nitazoxanide reduces the levels of HIF2 by increasing the levels of PHD3, the prolyl hydroxylase that degrades HIF2.

molecular biology↗