Nrf2 modulates cytosolic and mitochondrial calcium signal

Alessandra Preziuso, Artyom Y. Baev, Fozila R. Rustamova, Sharadha Dayalan Naidu, Lauren Millichap, Plamena R. Angelova, Vincenzo Lariccia, Albena T. Dinkova-Kostova, Andrey Y. Abramov, Nrf2 modulates cytosolic and mitochondrial calcium signal, Redox Biology, Volume 94, 2026, 104213, ISSN 2213-2317, doi:10.1016/j.redox.2026.104213.

Here, using primary co-cultures of neurons and astrocytes we asked if Nrf2 activation or deficiency alters physiological Ca2+ signaling and mitochondrial Ca2+ handling in brain cells. We found that activation of Nrf2 leads to an increase in the amplitude of Ca2+ peak and a faster Ca2+efflux in response to glutamate and ATP in neurons and astrocytes. Interestingly, Nrf2-deficient neurons and astrocytes also had higher Ca2+ peaks in response to glutamate and ATP, but the recovery in neurons was significantly delayed. Genetic (Keap1-knockdown) or pharmacological (ovameloxolone, RTA-408) activation of Nrf2 increases mitochondrial Ca2+ uptake and mitochondrial Ca2+ capacity, and this correlates with increased activity of the Na+/Ca2+/Li+ exchanger (NCLX) and inhibition of the mitochondrial permeability transition pore (mPTP). Conversely, mitochondria in neurons and astrocytes from Nrf2-knockout mice had a lower Ca2+ uptake, lower mitochondrial Ca2+ capacity and lower mitochondrial Ca2+efflux, making these cell vulnerable to Ca2+-induced cell death. Thus, Nrf2 modulates cytosolic calcium signaling and activates the mitochondrial NCLX, increasing the mitochondrial Ca2+ capacity, which adds another critical aspect to the multifaceted nature of Nrf2-mediated cytoprotection.

The importance of this research lies in providing a key scientific foundation, demonstrating that omaveloxolone not only reduces oxidative stress but also directly protects neurons by correcting mitochondrial calcium defects—a critical process that is impaired in patients with Friedreich's Ataxia.

LEXEO THERAPEUTICS ANNOUNCES REGULATORY UPDATE AND REGISTRATIONAL TRIAL DESIGN FOR LX2006 GENE THERAPY IN FRIEDREICH ATAXIA

NEW YORK, June 15, 2026 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, today announced that the Company has finalized the SUNRISE-FA 2 pivotal trial protocol and statistical analysis plan (SAP) intended to provide clinical evidence to support the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for gene therapy candidate LX2006 under the accelerated approval pathway in 2028.

Drugging the ferroptotic landscape of Friedreich’s Ataxia: Current paradigms and future directions

Cravin G, Cozza G. Drugging the ferroptotic landscape of Friedreich’s Ataxia: Current paradigms and future directions. Ferroptosis Oxid Stress. 2026;2:202618. doi:10.70401/fos.2026.0032 

 In the present review, we explore how FXN loss undermines cellular defenses against oxidative damage, placing a specific focus on the regulation of the lipid redox landscape. We detail the breakdown of glutathione (GSH)-dependent mechanisms, specifically highlighting the blunted Nrf2 antioxidant response and the subsequent reduced capacity of glutathione peroxidase 4. Alongside these deficits, we investigate the compensatory roles of GSH-independent rescue networks, namely ferroptosis suppressor protein 1 and mitochondrial dihydroorotate dehydrogenase. Looking toward clinical translation, we critically assess emerging pharmacological interventions designed to target these ferroptotic nodes. The potential of mitochondria-targeted iron chelators, lipoxygenase inhibitors, lipophilic radical-trapping antioxidants, and novel Nrf2 activators is evaluated to determine whether inhibiting ferroptosis can serve as a viable disease-modifying strategy. Moving forward, combinatorial “protect and restore” approaches will likely prove essential for maximizing therapeutic efficacy in FRDA.

Transitional Life Events in Friedreich Ataxia: Differential Age at Onset Perspectives

Iskandar, A., Buchholz, M., Sarwinska, D. et al. Transitional Life Events in Friedreich Ataxia: Differential Age at Onset Perspectives. Cerebellum 25, 96 (2026). doi:10.1007/s12311-026-02038-7 

 The results underscore the importance of incorporating onset-specific considerations into clinical care and support strategies. Future studies should aim to gain a deeper understanding of the psychosocial burden of FA across the lifespan. By considering the unique pathways of patients in different life stages, researchers can tailor interventions to address differing illness perceptions across various age at onset. Comparative studies across different hereditary ataxias, such as spinocerebellar ataxias, could clarify whether the onset-dependent patterns we observed are specific to FA or represent broader features of progressive ataxic disorders. Moreover, qualitative approaches should complement quantitative measures to deepen insight into patients’ lived experiences, particularly regarding interpersonal challenges and the use of assistive devices. Finally, future intervention studies should include targeted psychosocial support, counselling, or stigma-reduction strategies can mitigate the adverse impact of relationship-related life events and improve mental wellbeing in FA, especially for those with pediatric onset.

AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial

Crystal RG, Weinsaft JW, Kaminsky SM, et al. AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial. JAMA Cardiol. Published online June 17, 2026. doi:10.1001/jamacardio.2026.1699 

In an open-label, dose-ranging, nonrandomized clinical trial of 17 patients, intravenous administration of AAVrh.10hFXN was associated with minimal toxic effects, reduced cardiac magnetic resonance imaging assessment of left ventricular mass index, and reduced serum high-sensitivity troponin I level.

Seventeen patients with FA cardiomyopathy (mean [SD] age, 25 [6] years; 11 [65%] female) were followed up for a mean (SD) of 20 (8) months. There were 4 serious adverse events, 3 possibly related to prednisone immunosuppression and 1 possibly vector-related myocarditis 12 months after therapy, all of which resolved. Other adverse events were transient, nonserious, or not treatment related. In all 8 patients with cardiac biopsy 3 months after therapy, there were higher levels of cardiac FXN (dose cohort 1, 20%; cohort 2, 81%; cohort 3, 123%). After therapy, LVMI was lower by at least 10% in 9 patients and stabilized in 8 patients. Excluding the patient with myocarditis, posttherapy values of serum hs troponin I were lower by at least 10% in 15 patients and higher by at least 10% in 2 patients.

Polyphenols in mtDNA Repair, Mitochondrial Biogenesis, and Mitophagy: An Integrative Review

Victoria-Montesinos, D., Barcina-Pérez, P., García-Muñoz, A.M. (2026). Polyphenols in mtDNA Repair, Mitochondrial Biogenesis, and Mitophagy: An Integrative Review. BIOCELL, 50(6), 2. doi:10.32604/biocell.2026.077286 

 Mitochondrial dysfunction is a central hallmark of metabolic, hepatic, cardiovascular, and neurodegenerative diseases. Dietary polyphenols modulate mitochondrial pathways, but their integrated effects remain poorly appreciated. This narrative review synthesizes preclinical and clinical evidence on four polyphenols (resveratrol, epigallocatechin-3-gallate, quercetin, and oleuropein) and examines their mechanisms in mitochondrial biogenesis, mtDNA protection, and mitophagy. Experimental studies indicate that these compounds activate conserved adaptive pathways, including sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), AMP-activated protein kinase (AMPK), and PTEN-induced kinase 1 (PINK1) with Parkin, therapy enhancing mitochondrial biogenesis, reducing oxidative stress, and promoting selective removal of damaged mitochondria

Genetic modifiers of Friedreich's ataxia pathophysiology in Drosophila melanogaster - A systematic review and meta-analysis

Ravi Kant Yadav, Vishnu Swarup, Anami Ahuja, Dipesh Talukdar, Divyani Garg, Muraleedhar Aski, Achal Kumar Srivastava, Prachi Yadav, Genetic modifiers of Friedreich's ataxia pathophysiology in Drosophila melanogaster - A systematic review and meta-analysis, Free Radical Biology and Medicine, Volume 254, 2026, Pages 196-210,, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2026.06.031. 

 Ferritins overexpression, Miro inhibition, and catalase overexpression, converging pathways iron homeostasis, mitochondrial dynamics and oxidative stress management, were found to be the top ranked modifiers for their beneficial effects on FRDA pathophysiology and were suggested for further studies as therapeutic targets.

Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model

Lees, J.G., Zhang, H., Jiao, L. et al. Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model. Cell Death Dis (2026). doi:10.1038/s41419-026-09030-3

 RNA sequencing revealed a distinct transcriptional profile associated with frataxin deficiency. MEG3 and PCDHGA10 were consistently dysregulated across all three FRDA-iPSC lines and may represent early molecular markers of FRDA cardiomyopathy. Functional interrogation of these candidates demonstrated that targeted silencing of MEG3 or PCDHGA10 in FRDA cardiomyocytes significantly reduced disease‑associated cell death without affecting FXN expression. Notably, PCDHGA10 silencing also normalized elevated mitochondrial reactive oxygen species, whereas MEG3 silencing did not, highlighting gene‑specific contributions to FRDA cardiomyocyte survival. Collectively, these findings identify MEG3 and PCDHGA10 as functionally relevant regulators of FRDA cardiomyocyte pathology.

Dysregulation of sphingolipid-metabolizing enzymes in Friedreich’s ataxia: In vitro and in vivo insights into therapeutic targeting

Ramchunder Z, Kalef-Ezra E, Suleman S ..., Dysregulation of sphingolipid-metabolizing enzymes in Friedreich’s ataxia: In vitro and in vivo insights into therapeutic targeting, iScience, 2026; 29. DOI: 10.1016/j.isci.2026.116479 

 Sphingolipids are increasingly recognized for their roles in neurodegeneration with emerging evidence indicating their dysregulation in FRDA. Here, we investigate whether sphingolipid-metabolizing enzymes are similarly affected and assess the therapeutic potential of targeting them. Our findings demonstrate that these enzymes are dysregulated across multiple FRDA models. Importantly, their modulation in vitro and in vivo significantly reduces mitochondrial dysfunction, enhances frataxin expression, and improves key pathological features of the disease, highlighting sphingolipid metabolism as a promising therapeutic target for FRDA.

Limiting intestinal iron absorption rescues glial defects and extends lifespan in a Drosophila model of Friedreich ataxia

Limiting intestinal iron absorption rescues glial defects and extends lifespan in a Drosophila model of Friedreich ataxia Ema TURKI, Estelle JULLIAN, Pierre DELAMOTTE, Anne FILIPE, Laura TIXIER CARDOSO, Sandrine MIDDENDORP, Elodie MARTIN, Veronique Monnier bioRxiv 2026.06.04.730074; doi:10.64898/2026.06.04.730074 

 Reducing intestinal iron uptake, either through treatment with bathophenanthroline disulfonic acid (BPS), an extracellular iron chelator, or by gut-specific silencing of the iron transporter Malvolio, nearly doubled fly survival. BPS treatment also improved sensitivity to dietary iron, enhanced locomotor performance, fully restored normal brain size, and prevented glial alterations. Altogether, our findings identify glial cells as early and preferential targets of frataxin deficiency in an iron-dependent manner and support the in vivo relevance of intestinal iron uptake as a potential modulator of disease severity in FRDA.