Mitochondrial Oxidative Stress and Cardiac Dysfunction in TERT Deficient Progeria Mice

Area of Science:

• Cardiology
• Gerontology
• Mitochondrial Biology

Background:

• Heart failure (HF) is a significant cause of hospitalization in the elderly, with incidence increasing with age and risk factors like hypertension and diabetes.
• Aging-related myocardial fibrosis impairs cardiac function, but mechanisms linking mitochondrial oxidative stress to cardiac remodeling in aging remain unclear.

Purpose of the Study:

• To investigate the mechanisms of aging-related ventricular electrical and structural remodeling.
• To determine the role of mitochondrial dysfunction in aging-associated heart failure.

Main Methods:

• Developed third-generation telomerase reverse transcriptase deficient (TERT-/-) progeria mice to model accelerated aging.
• Utilized echocardiography, histology, electrocardiography, epicardial mapping, RNA sequencing, and biochemical assays to assess cardiac function and remodeling.

Main Results:

• TERT-/- mice showed accelerated aging, with increased p53, interstitial fibrosis, and inflammation, indicating structural remodeling.
• Significant systolic and diastolic dysfunction, prolonged QRS duration, and slowed ventricular conduction velocity demonstrated electrical remodeling.
• Mitochondrial oxidative stress pathways were upregulated, with disrupted mitochondrial ultrastructure and altered protein expression, highlighting mitochondrial dysfunction's role.

Conclusions:

• Accelerated aging in TERT-/- mice leads to significant cardiac impairments, including electrical and structural remodeling, driven by mitochondrial dysfunction and oxidative stress.
• Mitochondrial oxidative stress is implicated in aging-related heart failure.
• Targeting mitochondrial quality control presents a potential therapeutic strategy for aging-related heart failure.