Journal article
Mitochondrial Calcium Uniporter Regulates Metabolic Remodeling and Smooth Muscle Cell Proliferation in Type 2 Diabetes
Journal of the American Heart Association, Vol.14(15), e039220
08/05/2025
DOI: 10.1161/JAHA.124.039220
PMCID: PMC12449995
PMID: 40673552
Appears in UI Libraries Support Open Access
Abstract
Excessive proliferation of vascular smooth muscle cells (VSMCs) is a consequence of type 2 diabetes (T2D) that increases the risk for atherosclerosis and restenosis after angioplasty. Here, we sought to determine whether and how mitochondrial dysfunction in T2D drives VSMC proliferation with a focus on increased reactive oxygen species and intracellular [Ca
] that both drive cell proliferation, occur in T2D, and are regulated by the mitochondrial Ca
uniporter (MCU).
Using a mouse model of T2D, we performed in vivo phenotyping after mechanical injury and established the mechanisms of excessive proliferation in cultured VSMCs. The T2D model was induced by high-fat diet and low-dose streptozotocin in both wild type mice and mice with the VSMC-specific inhibition of the mtCaMKII (mitochondrial Ca
/calmodulin-dependent kinase IImtCaMKII), a regulator of Ca
entry via the MCU.
In VSMCs from T2D model mice, MCU inhibition reduced both in vivo neointima formation after mechanical injury, as well as in vitro proliferation of cultured VSMCs. Further, in VSMCs from T2D mice, the composition of the MCU complex and MCU activity were altered with loss of MICU1 (mitochondrial calcium uptake 1). In addition, VSMC mitochondrial reactive oxygen species was elevated and mitochondrial respiration blunted. The increase in cytosolic reactive oxygen species induced activation of G6PD (glucose-6-phosphate dehydrogenase), a key enzyme of the pentose phosphate pathway. However, inhibiting MCU or MICU1 overexpression on VSMCs from T2D mice decreased intracellular reactive oxygen species, preserved mitochondrial respiration and ATP production, decreased activity of G6PD, and normalized cell proliferation. These data suggest the MCU complex controls a T2D-induced metabolic switch that promotes cell proliferation.
Collectively, these data indicate that MCU complex remodeling in T2D drives neointimal restenosis, suggesting MCU as a therapeutic target.
Details
- Title: Subtitle
- Mitochondrial Calcium Uniporter Regulates Metabolic Remodeling and Smooth Muscle Cell Proliferation in Type 2 Diabetes
- Creators
- Olha M Koval - University of IowaEmily K Nguyen - University of IowaDylan J Mittauer - University of IowaJane L Buchanan - University of IowaKyle Westhoff - University of IowaDao-Fu Dai - University of IowaEric B Taylor - University of IowaIsabella M Grumbach - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.14(15), e039220
- DOI
- 10.1161/JAHA.124.039220
- PMID
- 40673552
- PMCID
- PMC12449995
- NLM abbreviation
- J Am Heart Assoc
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Publisher
- Wiley
- Grant note
- National Institutes of HealthResearch Communication Core at the University of Iowa Carver College of Medicine
The authors thank Dr Christine Blaumueller of the Scientific Editing and Research Communication Core at the University of Iowa Carver College of Medicine and Diana Colgan for critical reading of the article.
- Language
- English
- Electronic publication date
- 07/17/2025
- Date published
- 08/05/2025
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984847998902771
Metrics
8 Record Views