Biology subjects

Purandare, N.

Publications and source records attributed to Purandare, N..

7 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↗

bioRxiv2025

Relationship between melanoma vemurafenib tolerance thresholds and metabolic pathway choice and Wnt signaling involvement

Vemurafenib constitutes an important therapeutic for BRAFV600 mutant melanomas, but despite high initial response rates, resistance to BRAF and MEK inhibitors quickly develops. Here, we performed an integrative analysis of metabolomic consequences and transcriptome alterations to uncover mechanisms involved in adaptive vemurafenib resistance (VemR) development and their relationship with vemurafenib tolerance thresholds. We developed BRAFV600E isogenic models of VemR utilizing M14 and A2058 lines, and patient-derived melanomas with V600E or normal BRAF to verify vemurafenib selectivity. MEK or PI3K inhibitors only partially inhibited VemR cell proliferation, indicating cross-resistance to these inhibitors. MITF and {beta}-catenin levels were induced and treatment with Wnt/{beta}-catenin inhibitor ICG-001 restored vemurafenib sensitivity with concomitant reductions in {beta}-catenin-regulated gene expressions, phospho-ERK1/2, and VemR-induced mitochondrial mass and respiration. Targeted metabolite, MitoPlate-S1, Mito-stress and transcriptome/metabolomic analysis showed that melanoma cells with elevated vemurafenib tolerance thresholds such as A2058 VemR cells utilize Wnt/{beta}-catenin signaling for mitochondrial metabolism while VemR cells with low tolerance such as M14 VemR cells rely on Wnt/{beta}-catenin signaling for pentose phosphate pathway. Pathways associated with cytokine-cytokine receptor, ECM receptor, and neuroactive ligand receptor interactions were similarly enriched in BRAFV600E patient-derived melanoma as M14 and A2058 cells whereas distinct pathways involving cell cycle, DNA replication, Fanconi anemia and DNA repair pathways are upregulated in wild type BRAF expressing patient derived melanoma. These data show for the first time that the metabolic pathway choices made by VemR BRAF mutant melanomas are controlled by vemurafenib tolerance and endurance thresholds and Wnt/{beta}-catenin signaling plays a central role in coordinating expression of genes controlling VemR and metabolic pathway shifts.

cancer 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↗

bioRxiv2024

Impact of genomic background and developmental state on signaling pathways and response to therapy in Glioblastoma patient-derived cells

Glioblastoma (GBM) tumors represents diverse genomic epigenomic, and transcriptional landscapes, with significant intratumoral heterogeneity that challenges standard of care treatments involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed targeted proteomics to assess the response of a genomically-diverse panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation, growth factor withdrawal and traditional high fetal bovine serum culture. Our findings revealed a complex crosstalk and co-activation of key oncogenic signaling in CSCs and diverse patterns of response to these external stimuli. Using RNA sequencing and DNA methylation, we observed common adaptations in response to astrocytic differentiation of CSCs across genomically distinct models, including BMP-Smad pathway activation, reduced cholesterol biosynthesis, and upregulation of extracellular matrix components. Notably, we observed that these differentiated CSC progenies retained a subset of stemness genes and the activation of cell survival pathways. We also examined the impact of differentiation state and genomic background on GBM cell sensitivity and transcriptional response to TMZ and RT. Differentiation of CSCs increased resistance to TMZ but not to RT. While transcriptional responses to these treatments were predominantly regulated by p53 in wild-type p53 GBM cells, its transcriptional activity was modulated by the differentiation status and treatment modality. Both mutant and wild-type p53 models exhibited significant activation of a DNA-damage associated interferon response in CSCs and differentiated cells, suggesting this pathway may play a wider role in GBM response to TMZ and RT. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.

cancer biology↗

bioRxiv2023

MNRR1 activation by nitazoxanide abrogates lipopolysaccharide- induced preterm birth in mice

Intra-amniotic inflammation leading to preterm birth is one of the leading causes of neonatal morbidity and mortality. We recently found that the mitochondrial levels of MNRR1 (Mitochondrial Nuclear Retrograde, Regulator 1; also called CHCHD2, AAG10, or PARK22), an important bi-organellar regulator of cellular function, are reduced in the context of inflammation and that both genetic and pharmacological increase in MNRR1 levels can counter the inflammatory profile. We show here that nitazoxanide, a clinically-approved drug, is an activator of MNRR1 and prevents preterm birth in a well-characterized murine model caused by intra-amniotic lipopolysaccharide (LPS) injection. HighlightsO_LINitazoxanide exerts anti-inflammatory functions via activation of MNRR1. C_LIO_LIOral administration of nitazoxanide prevents preterm birth in mouse model of intra-intraamniotic LPS-induced inflammation. C_LI

immunology↗

bioRxiv2021

Lipopolysaccharide induces placental mitochondrial dysfunction by reducing MNRR1 levels via a TLR4-independent pathway

Mitochondria play a key role in the growth and development of the placenta, an organ essential for pregnancy in eutherian mammals. Mitochondrial dysfunction has been associated with pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals at a cellular and mechanistic level are unknown. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) is a bi-organellar protein responsible for optimal mitochondrial function to achieve energy and redox homeostasis. In addition, MNRR1 also is required for optimal induction of cellular stress-responsive signaling pathways such as the mitochondrial unfolded protein response (UPRmt). Here, in a lipopolysaccharide-induced model of placental inflammation, we show that MNRR1 levels are reduced in placental tissues and cell lines. Reduction in MNRR1 is associated with mitochondrial dysfunction and enhanced oxidative stress along with activation of pro-inflammatory signaling. Mechanistically, we uncover a non-conventional pathway independent of Toll-like receptor 4 (TLR4) that results in a specific ATM kinase-dependent threonine phosphorylation and activation of a mitochondrial protease, YME1L1, degrading MNRR1. Furthermore, enhancing MNRR1 levels in placental cells either genetically or with specific activators abrogates the bioenergetic defect and induces an anti-inflammatory phenotype, suggesting that MNRR1 is upstream of the mitochondrial dysfunction observed in our model. Reduction in MNRR1 levels is a generalized phenomenon observed in cells under an inflammatory stimulus. We therefore propose MNRR1 as a novel anti-inflammatory therapeutic target in pathologies associated with placental inflammation.

molecular biology↗