# Age-Related Decrease in Mitofusin 1 Results in Platelet Dysfunction and Thrombosis

> **NIH NIH K99** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $162,852

## Abstract

PROJECT SUMMARY/ABSTRACT
Aging is one of the greatest risk factors for thrombotic diseases such as deep vein thrombosis, myocardial
infarction and stroke. Platelets are central to thrombus formation through their activation and aggregation. Prior
studies show age-dependent increases in platelet activation, but the molecular mechanisms remain unknown.
Though platelets are anucleate they contain functional mitochondria and an active ubiquitin-proteosome system
(UPS). The UPS removes old and damaged proteins to maintain cellular homeostasis. Our preliminary data
suggests that platelets isolated from healthy aged (>75 years) human subjects show increased UPS activity and
decreased expression of the key mitochondrial fusion protein mitofusin 1 (MFN1) compared to platelets isolated
from healthy young subjects (18-35 years). Platelets from aged individuals also exhibited increased
mitochondrial oxidant production and platelet activation. Based on these observations, we will test the
hypothesis that age-dependent changes in the UPS lead to increased mitochondrial dysfunction
resulting in mitochondrial reactive oxygen species (mtROS) production to stimulate platelet activation
and subsequent thrombosis. In Aim 1, we will characterize the UPS in isolated platelets from young and aged
healthy human subjects. Concomitant MFN1 levels and platelet activation measurements will be made to
determine how these systems are altered by the age-related changes in the UPS. To establish a murine model
for molecular mechanism, we will perform identical measurements in young (8-10 week) and aged (>1.5 year)
wildtype (WT) mice. These studies will be complemented by an in vitro cell culture system of human derived
CD34+ progenitor cells which can be differentiated into platelets and used for mechanistic studies that utilize
lentivirus to specifically target the UPS components. In Aim 2, we generated platelet-specific MFN1 knockout
(KO) mice to determine whether decreased MFN1 in platelets results in increased mtROS and susceptibility to
thrombosis. We will measure changes in platelet morphology, mtROS production, and mitochondrial
bioenergetics in young and aged platelet-specific MFN1 KO mice and compare it to young and aged WT mice.
Adenovirus will be used to overexpress MFN1 in old WT and platelet-specific MFN1 KO mice to determine if it
rescues the aged phenotype. Additionally, young and aged WT and platelet-specific MFN1 (KO) mice will be
subject to laser-induced vascular injury to determine if platelet activation and thrombosis susceptibility increases
when MFN1 is absent. Lentivirus knockdown and overexpression of MFN1 in our CD34+ cell culture system will
complement these mechanistic studies. Finally, Aim 3 will determine whether the clinically used drugs MitoQ
(mtROS scavenger) or Bortezomib (proteasome inhibitor) can attenuate age-dependent platelet activation and
thrombosis in WT and platelet-specific MFN1 KO murine models. Successful completion of this project wi...

## Key facts

- **NIH application ID:** 10260550
- **Project number:** 5K99HL150166-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Andrea Catherine Braganza
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $162,852
- **Award type:** 5
- **Project period:** 2020-09-10 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260550

## Citation

> US National Institutes of Health, RePORTER application 10260550, Age-Related Decrease in Mitofusin 1 Results in Platelet Dysfunction and Thrombosis (5K99HL150166-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10260550. Licensed CC0.

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