Glycative Stress Disrupts the Mitochondrial-Lysosome Axis and Promotes Geroconversion in Aging Cardiomyocytes

Area of Science:

• Cardiovascular Biology
• Aging Research
• Mitochondrial Biology

Background:

• Aging is a primary risk factor for heart failure, but underlying molecular mechanisms are unclear.
• Mitochondrial dysfunction and impaired organelle quality control are key features of the aging heart.

Purpose of the Study:

• To investigate the role of advanced glycation end products (AGEs) in cardiac aging and heart failure.
• To elucidate the biochemical mechanisms linking mitochondrial dysfunction, inflammation, and senescence in the aging heart.

Main Methods:

• Comprehensive glycomics analysis of cardiac mitochondria from aged mice.
• In vitro studies using H9c2 myoblasts exposed to glycative stress.
• Assessment of mitochondrial function, lysosomal activity, and cellular senescence.

Main Results:

• Cardiac mitochondria from aged mice accumulate significant levels of AGEs, correlating with mild dysfunction.
• AGE-modified mitochondria impair lysosomal acidification and proteolysis, hindering mitophagy.
• This process leads to lipofuscin accumulation and induces proinflammatory senescence in cardiomyocytes.

Conclusions:

• Mitochondrial AGE accumulation is a novel mechanism driving aging-associated stress and cellular senescence in the heart.
• Impaired mitochondrial-lysosomal crosstalk due to AGEs contributes to the aging heart's transition towards a failing phenotype.