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.

Chemical modulation of Miro1 alleviates cell-type-specific vulnerabilities in Friedreich’s ataxia

Chandra S, Kwak C, Du Z ... Chemical modulation of Miro1 alleviates cell-type-specific vulnerabilities in Friedreich’s ataxia, Cell Chemical Biology, 2026; 0.  DOI: 10.1016/j.chembiol.2026.05.004

MR3 treatment modulates molecular signatures in a cell-type-dependent manner, altering pathways related to cardiac contractility in cardiomyocytes and synaptic function in sensory neurons. Mechanistically, MR3 reduces mitochondrial reactive oxygen species and restores membrane potential in FA sensory neurons via potential allosteric reshaping of Miro1 protein. We expand the chemical diversity of this scaffold by conducting ligand-based virtual screening of over 3 billion compounds and identifying previously uncharacterized Miro1 ligands with improved docking and neuroprotective capacity.

Anodal cerebellar tDCS does not alter beta oscillations or corticokinematic coherence in Friedreich’s ataxia and healthy participants

Christian Georgiev, Mathieu Bourguignon, Scott J. Mongold, Lousin Moumdjian, Pierre Cabaraux, Gilles Naeije, Anodal cerebellar tDCS does not alter beta oscillations or corticokinematic coherence in Friedreich’s ataxia and healthy participants, Clinical Neurophysiology, Volume 190, 2026, 2111961, ISSN 1388-2457, doi:10.1016/j.clinph.2026.2111961. 

Anodal ctDCS improved FA motor symptom severity without altering SM1 excitability. 

Anodal ctDCS has a therapeutic effect in FA, however, the neurophysiology of this effect is complex and requires further investigation.

New Progress Toward Public Reimbursement of SKYCLARYS™ for People Living with Friedreich Ataxia in Quebec

TORONTO, June 8, 2026 /CNW/ - Biogen Canada Inc. is pleased to announce a positive outcome from the Institut national d'excellence en santé et en services sociaux (INESSS) re-evaluation of SKYCLARYS™ (omaveloxolone), recognizing the therapeutic value of the treatment and establishing reimbursement criteria for eligible patients living with Friedreich ataxia (FA) in Quebec. This outcome represents a positive step toward public reimbursement in the province for the only approved treatment in Canada for Friedreich ataxia.

MRI end-points for clinical trials in ataxias: recommendations from the Ataxia Global Initiative MRI Biomarkers Working Group

Öz, G., Cocozza, S., Rezende, T.J.R. et al. MRI end-points for clinical trials in ataxias: recommendations from the Ataxia Global Initiative MRI Biomarkers Working Group. Nat Rev Neurol (2026). doi:10.1038/s41582-026-01218-7 

In this Consensus Statement, the Ataxia Global Initiative MRI Biomarkers Working Group critically reviews candidate MRI end-points for trials in the most common spinocerebellar ataxias (SCA1, SCA2 and SCA3) and Friedreich ataxia and provides evidence-based, disease-specific recommendations for the selection of MRI end-points for trials in these diseases.