Aging is a major risk factor for heart failure, yet the molecular mechanisms linking cardiac aging to the inflammatory pathophysiology of heart failure remain elusive. Mitochondrial dysfunction and defective organelle quality control are emerging hallmarks of the aging heart, but their biochemical underpinnings are poorly defined. Using comprehensive glycomics, we found that cardiac mitochondria from physiologically aged mice (≥ 20 months) are the major intracellular reservoirs of advanced glycation end products (AGEs), derived primarily from the chemical attack of some α-oxoaldehydes on proteins. This was associated with mild mitochondrial dysfunction and structural remodeling. Lysosomes in aged hearts were enlarged, more abundant, less acidic, and frequently loaded with lipofuscin. Notably, ~7% of cardiomyocytes showed proinflammatory senescence traits. In vitro, glycative stress in H9c2 myoblasts reproduced mitochondrial AGE buildup, dysfunction, and activation of the mitochondria-lysosome axis. However, AGE-modified mitochondria impaired lysosomal acidification and proteolysis, hindering mitophagic clearance and contributing to lipofuscin accumulation. This sequence of events ultimately led to proinflammatory senescence in a subset of cells. These findings identify mitochondrial AGE accumulation as a novel mechanism of sublethal nonsolved aging-associated stress that eventually triggers geroconversion in cardiomyocytes. This mechanism could facilitate the transition of the aging heart towards a failing phenotype.
Bou‐Teen et al. (Sun,) studied this question.