Omics · study · 2026
LMNA p.H222P mutation causes contractile dysfunction via impaired mitochondrial calcium uptake in human cardiac laminopathy
Listed in NCBI GEO
Mutations in the LMNA gene, encoding lamin A/C, are implicated in laminopathies and can lead to dilated cardiomyopathy and heart failure.
Description
However, the underlying mechanisms remain unclear. Here, we generated human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) from a patient carrying the LMNA p.His222Pro (c.665A>C) mutation and an isogenic CRISPR/Cas9-corrected control.
Although differentiation efficiency and sarcomere organization were comparable, 3D cardiac organoids composed of LMNA mutant hiPSC-CMs displayed significantly reduced contractility compared to control organoids. Transcriptomic, biochemical and functional analyses revealed impaired mitochondrial calcium uniporter (MCU) complex activity in LMNA mutant hiPSC-CMs, marked by decreased MCU expression, an elevated MICU1:MCU ratio, and increased phosphorylation of pyruvate dehydrogenase (PDH) at Ser232 and PDH Ser300 – indicative of reduced mitochondrial calcium uptake.
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These defects were accompanied by decreased mitochondrial respiration and ATP production. Notably, treatment with the MCU activator amorolfine restored mitochondrial calcium uptake and contractility in LMNA mutant hiPSC-CMs. These findings identify mitochondrial calcium dysregulation as a key downstream consequence of the LMNA p.H222P mutation.
Our results establish a mechanistic link between LMNA-associated cardiomyopathy and impaired mitochondrial function, highlighting the MCU complex as a potential therapeutic target in human cardiac laminopathy.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE304nnn/GSE304575 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304575 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1301814 ncbi.nlm.nih.gov/bioproject/PRJNA1301814 ↗
project · from NCBI GEO
- PubMed 42478871 pubmed.ncbi.nlm.nih.gov/42478871 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cardiomyopathy 75% · Heart 75%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE304575 | 15 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[anatomy].local:anatomy:heart | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[disease].local:disease:cardiomyopathy | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |