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Mitochondrial superoxide-mediated mitohormesis protects against doxorubicin-induced cardiotoxicity [AcuteDoxo_RNAseq]

GSE313129 Mus musculus (mouse) RNA-seq (gene expression) 12 samples Submitted 2026/05/31 Platform GPL34290

At a glance

RNA-seq (gene expression) · mouse · 12 samples

What it is: RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism: Mus musculus (mouse)
Samples: 12 samples: 4 × Control+Doxorubicin vs 3 × iSOD2 Untreated vs 3 × iSOD2+Doxorubicin vs 2 × Control UntreatedGroups are read from the sample names, not from the paper. Check the list below.
Data you can get: A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.

Summary (written by the submitters)

Transient mitochondrial stress, even if only experienced in early development, paradoxically increases lifespan and confers future stress protection in a process termed mitohormesis. However, whether mitohormesis functions in the heart to prevent pathology driven by mitochondrial and oxidative injury has not been tested. While mitohormesis requires coordinated transcriptional and chromatin-level remodeling, the mitochondrial signals initiating these responses in mammals have not been fully defined.

Read the full summary ↓

Using the iSOD2 mouse model of mitohormesis we previously developed, we show that SOD2 knockdown and accumulation of mitochondrial superoxide during embryogenesis results in adult hearts with enhanced mitochondrial biogenesis and antioxidant enzyme expression. Furthermore, these mitohormetic adaptations prevented cardiac dysfunction and remodeling in acute and chronic models of doxorubicin-induced cardiotoxicity (DIC) by preserving mitochondrial integrity and mitigating oxidative damage. In a mouse embryonic fibroblast model of mitohormesis, we found transient SOD2-knockdown resulted in similar mitohormetic outcomes to those in heart, including increased mitochondrial biogenesis and antioxidant responses, histone acetylation, and resistance to doxorubicin-induced cell death. In this model, mitochondrial matrix superoxide inhibited the tricarboxylic acid cycle enzyme aconitase (ACO2), thereby redirecting its substrate citrate into the cytosol where it is converted by ACLY to acetyl-CoA for histone acetylation. Thus, we conclude that citrate is a redox-sensitive second messenger of mitochondrial superoxide stress that initiates this form of mitohormesis. Supporting this conclusion, genetic loss of the mitochondrial citrate transporter, SLC25A1, prevented the mitohormetic response, while knockdown of ACO2 or addition of exogenous citrate recapitulated the superoxide- mediated adaptations. We speculate this redox-sensitive mitohormetic signaling pathway might illuminate new therapeutic approaches for DIC and possibly other pathology involving mitochondrial defects and oxidative stress.

This dataset

Open GSE313129 in finder → Find more mouse RNA-seq datasets →

Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓

2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE313129_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓

3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1378563 and SRA study SRP653958. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗

Study design

4 × Control+Doxorubicin vs 3 × iSOD2 Untreated vs 3 × iSOD2+Doxorubicin vs 2 × Control Untreated

Supports a between-group comparison across 12 samples.

How we read this: 4 replicated groups read from 12 sample titles; they account for 12 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

GSM9362408 Control Untreated 1 Control Untreated
GSM9362409 Control Untreated 2 Control Untreated
GSM9362410 Control+Doxorubicin 4 Control+Doxorubicin
GSM9362411 Control+Doxorubicin 1 Control+Doxorubicin
GSM9362412 Control+Doxorubicin 2 Control+Doxorubicin
GSM9362413 Control+Doxorubicin 3 Control+Doxorubicin
GSM9362414 iSOD2 Untreated 1 iSOD2 Untreated
GSM9362415 iSOD2 Untreated 2 iSOD2 Untreated
GSM9362416 iSOD2 Untreated 3 iSOD2 Untreated
GSM9362417 iSOD2+Doxorubicin 1 iSOD2+Doxorubicin
GSM9362418 iSOD2+Doxorubicin 2 iSOD2+Doxorubicin
GSM9362419 iSOD2+Doxorubicin 3 iSOD2+Doxorubicin

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