Mito.newsMito.news
← All articlesEditorial brief · abstract-levelScore 90/100Confidence high
biorxiv2026-10-11Friedreich ataxiafrataxiniron-sulfur assemblyautonomic neurons

Frataxin-deficient autonomic neurons fire five-fold more spikes, raise mitochondrial ROS, and de-repress MEG3

Lees, Zhang, Dottori, Napierala and colleagues show that hyperexcitability is a cell-autonomous property of human Friedreich ataxia autonomic neurons, not only a downstream consequence of dying heart or gut tissue. Frataxin is the mitochondrial iron-delivery protein for iron-sulfur cluster assembly. The cultures keep low FXN mRNA and protein, raise mitochondrial reactive oxygen species, shift from networked to tubular mitochondria, and die more. The authors do not report cluster nuclearity, so the bioinorganic frame is frataxin loss and mitochondrial oxidant load, not a measured [2Fe-2S] or [4Fe-4S] occupancy.

Mito.news · at a glance

Signal profile (abstract-level)

Friedreich ataxia · frataxin · iron-sulfur assembly · autonomic neurons

Score 90/100BIORXIVhigh confidenceFriedreich ataxia
90
Importance
65
Mito signal
95
Dysfunction
75
Evidence
65
Translational

Editorial signal profile from the abstract (importance score, mito keywords, dysfunction tags, evidence density, translational cues). Not a figure reproduced from the preprint PDF.

Lees and colleagues built a human autonomic neuron from Friedreich ataxia induced pluripotent stem cells and from CRISPR-corrected isogenic controls. The FRDA neurons still make too little frataxin. They fire about five times as many spikes, pack those spikes into longer bursts, die more, and carry more mitochondrial reactive oxygen species. Mitochondria shift from a networked reticulum toward tubules. That is a cell-autonomous electrical and mitochondrial phenotype, not a second-hand effect of a failing heart.

Metal sites and redox

Frataxin is the mitochondrial iron chaperone that feeds the ISC assembly line. In Holm language, biological Fe-S sites are discrete cluster cores with defined nuclearity and core oxidation levels: [2Fe-2S]2+/+, [4Fe-4S]2+/+, aconitase-type 4Fe to 3Fe conversion, Rieske [2Fe-2S], heme Fe3+/Fe2+, and CuA/CuB in Complex IV. This paper does not inventory those cores. It reports frataxin protein down, mitochondrial ROS up, and morphology changed. The honest assignment is an ISC-assembly defect inferred from the gene, plus an oxidant load measured with mitochondrial ROS probes. Superoxide versus hydrogen peroxide is not separated. Complexes I-IV, ferrochelatase, NFS1/ISCU, and mitoNEET are not named as the failing sites.

What was measured

Three isogenic pairs. Autonomic lineage markers. FXN mRNA and frataxin protein. Spike counts, interspike intervals, burst length. Cell death. Mitochondrial ROS. Mitochondrial shape. Bulk RNA-seq, with MEG3 the top differentially expressed gene and coordinated de-repression of maternal noncoding transcripts at 14q32 DLK1-DIO3. A 43-gene imprinted-gene test did not light up other domains.

Caveats

These are cultured neurons. Autopsy degeneration of cardiac conduction ganglia is the clinical backdrop, not the assay. MEG3 is a locus hit, not a demonstrated driver of hyperexcitability. Do not write a specific [4Fe-4S] occupancy change into a database from this abstract.

What to do with it

Use this when a bot needs a human FRDA autonomic model that already has mitochondrial ROS and firing as paired readouts. The chemistry to chase next is which Fe-S enzyme actually lost its cluster, and whether restoring that cofactor silences the five-fold spike excess.

Free HTML is above. Bots pay for JSON at /api/v1/papers/10-64898-2026-10-06-757136. Optional wallet tester: MetaMask ($0.005).

Source preprint

Autonomic neurons are intrinsically hyperexcitable in a Friedreich ataxia iPSC model

10.64898/2026.10.06.757136

Lees JG, Zhang H, Li L, Dottori M, Pébay A, Corben L, Delatycki M, Wilcox S, Pullin JM, Choi J, McCarthy D, Napierala JS, Napierala M, Lim SY.

Open on biorxiv →PDF