Mitochondria-targeted therapy to improve metabolic health post-menopause

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Anne Elizabeth Newell-Fugate
Organization: TEXAS A&M AGRILIFE RESEARCH
Fiscal Year: 2024
Award: $419,056
Funding agency: National Institute on Aging

SUMMARY
Mitochondrial dysfunction in post-menopausal women due to loss of estradiol (E2) alone or in combination with
age-induced accumulation of reactive oxygen species (ROS) may play a central role in development of
metabolic dysfunction-associated steatotic liver disease (MASLD). Impaired oxidative phosphorylation
(OXPHOS) and increased ROS production are linked to dysfunctional hepatic lipid metabolism and liver
steatosis. Despite the impact of age and E2 loss on mitochondrial function in post-menopausal women, there is
a lack of targeted therapies to treat menopause-associated hepatocellular mitochondrial dysfunction. Current
therapies for menopause, which include hormone replacement therapy (HRT) or selective estrogen receptor
modulators (SERMs), have adverse and off-target effects such as increased risk for gynecologic cancer and
deep vein thrombosis and stroke. Moreover, none of these treatments specifically target mitochondrial function.
New pharmaceuticals targeting hepatocellular mitochondrial function with or without E2 would reduce morbidity
due to metabolic disease and improve the quality of life for post-menopausal women. The long-term goal of
this research is to develop effective therapies to treat mitochondrial dysfunction in post-menopausal women.
The objective of this proposal is to determine if two distinct, targeted nanoparticles can improve mitochondrial
function in HepG2 cells cultured in MASLD-like conditions and in aged and E2-deficient female mice. The
central hypothesis is that two unique nanoparticles – one that works via the nucleus and one that works directly
at the mitochondria via E2 - can be delivered to improve mitochondrial function in aged and E2-deficient
hepatocytes whose function is impacted by MASLD. Co-Investigator Dr. Gaharwar has developed a new class
of molybdenum disulfide (MoS2) nanoflowers that scavenge ROS, increase transcription factor a mitochondria
(TFAM) protein and mitochondrial biogenesis, and yield increased OXPHOS/ATP production. Based on
preliminary data using poly(lactic-coglycolic acid)-poly(ethylene glycol)-triphenylphosphine (PGLA-PEG-TPP)
nanoparticles covalently bonded to E2 (mito-E2) which demonstrates that mito-E2 colocalizes with
mitochondrial (mt) estrogen receptor (ER) beta (β), it is predicted that mito-E2 will target mtERβ and mtER
alpha (a) to improve 𝛽 oxidation and ATP production and decrease ROS. The hypothesis will be tested with
two Aims: (1) Determine if MoS2 nanoflower and mito-E2 improve mitochondrial function in aged and E2-
deficient MASLD-like conditions; (2) Determine the molecular mechanisms of mito-E2 at mtERa and mtER𝛽 in
HepG2 cells cultured in MASLD-like conditions. It is expected that each of the nanoparticles will improve
mitochondrial function in MASLD-like HepG2 cells and in mouse menopause models through different but
complimentary mechanisms. This innovative proposal lays the foundation to develop nanoparticle therapeutics
to treat post-menopausal MASLD. Specifically targeting mitochondria will advance precision medicine and
improve quality of life in individuals suffering from age-related liver disease.

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