Endoplasmic reticulum stress-mediated mitochondrial dysfunction in aged hearts.

Area of Science:

• Cardiovascular Biology
• Mitochondrial Biology
• Aging Research

Background:

• Aging impairs mitochondrial electron transport chain (ETC) function, particularly in interfibrillar mitochondria (IFM).
• Mitochondria and endoplasmic reticulum (ER) maintain close contact, and ER stress can injure cardiac mitochondria.

Purpose of the Study:

• To investigate if ER stress contributes to age-related mitochondrial dysfunction in the heart.
• To explore the role of ER stress in the decline of mitochondrial function during aging.

Main Methods:

• Isolated subsarcolemmal mitochondria (SSM) and IFM from young (3 mo), middle-aged (18 mo), and old (24 mo) C57Bl/6 mouse hearts.
• Assessed ER stress, mitochondrial oxidative phosphorylation (OXPHOS), and quantified ETC complex subunit content via proteomics.
• Administered 4-phenylbutyrate (4-PBA) to old mice to evaluate ER stress attenuation and functional recovery.

Main Results:

• ER stress progressively increased with age, correlating with mitochondrial dysfunction in 24-month-old mice.
• Aged IFM (24 mo) showed decreased OXPHOS with reduced complex I and IV activity and lower complex I subunit content.
• 4-PBA treatment in aged mice reduced ER stress and improved mitochondrial function.

Conclusions:

• ER stress is a significant contributor to age-associated mitochondrial dysfunction in the heart.
• Targeting ER stress represents a potential therapeutic strategy to enhance cardiac mitochondrial health in aging.