Aging Hearts Lose ER-Mitochondria Links, Starving Cells of Lipids Needed for Cleanup

The aging heart is characterized by the progressive accumulation of enlarged, dysfunctional mitochondria in cardiomyocytes—a change long recognized but mechanistically underexplored. This study from Hong, Zeng, Ma, and colleagues (Cell Death & Differentiation, 2025) provides a detailed mechanistic account of how age-related loss of ER-mitochondria (ER-Mito) contact sites drives this pathology through disrupted lipid metabolism and failed autophagy.

Mitochondria depend on the ER for key phospholipids, particularly phosphatidylserine (PS), which is shuttled across ER-Mito membrane contact sites and then decarboxylated to phosphatidylethanolamine (PE) by the inner mitochondrial membrane enzyme PISD. PE is essential not only for mitochondrial membrane integrity but also for autophagosome biogenesis—the double-membrane vesicles that engulf and deliver damaged organelles to lysosomes for degradation. In aged cardiomyocytes, the researchers demonstrate that ER-Mito contact frequency is substantially reduced, limiting PS delivery to mitochondria. Compounding this, PISD activity is further suppressed because LACTB—a mitochondrial protease that negatively regulates PISD—accumulates with age. Together, these two hits produce a severe intramitochondrial PE deficit.

The downstream consequences are significant. Without adequate PE, autophagosome membranes cannot form efficiently, causing autophagic flux to stall. Damaged mitochondria that would normally be cleared via mitophagy instead persist, fuse into giant structures, and propagate oxidative and proteotoxic stress throughout the cardiomyocyte. This explains, at a molecular level, the canonical giant-mitochondria phenotype of the aged heart.

To validate the therapeutic relevance of this pathway, the team modulated LACTB expression in both naturally aging mouse heart tissue and an etoposide-induced cellular senescence model. Reducing LACTB de-repressed PISD, elevated PE production, restored autophagosome formation, cleared dysfunctional mitochondria, and preserved overall cardiomyocyte integrity. These rescue experiments provide strong causal evidence that the LACTB–PISD–PE axis is not merely correlative but functionally central to the aging cardiac phenotype.

The findings carry broad implications. First, they mechanistically link two well-known but previously disconnected hallmarks of cellular aging—loss of organelle contact sites and impaired autophagy—through a concrete lipid-metabolic intermediary. Second, they identify LACTB as a druggable node: small-molecule inhibitors of LACTB could in principle restore mitochondrial PE homeostasis and autophagic capacity in aging myocardium. Third, the work raises the possibility that other age-related diseases involving mitochondrial dysfunction and autophagy impairment (neurodegeneration, skeletal muscle sarcopenia) may share this ER-Mito lipid transport mechanism. Caveats include the primarily murine experimental base and the need for in vivo pharmacological validation of LACTB-targeting strategies before clinical translation.