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.
Read the rest (2 more)
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 | 14 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 |