With aging, the morphology and function of the parotid glands are impaired, and the current mechanism is unknown. The integrity of mitochondria-associated membranes (MAMs), the structure connecting mitochondria and the endoplasmic reticulum (ER), is compromised during aging. This study investigated the effects of aging on MAMs and ER stress in the parotid glands of mice. Here, aged mice presented abnormalities in gland morphology and mitochondrial morphology and reduced MAMs integrity. Protein kinase R-like endoplasmic reticulum kinase (PERK) signaling is the primary mediator of ER stress, which is activated in the parotid glands of aged mice. Furthermore, aging-induced MFN2 downregulation disrupts mitochondrial dynamics. In addition, aging reduces MAMs function by blocking the MFN2–PERK interaction. Treatment with 4-phenylbutyric acid (4-PBA) improved MAMs integrity, inhibited the PERK pathway, and reduced apoptosis. Like 4-PBA, GSK2606414, a pharmacological antagonist of PERK, regulates ER stress and MAMs. Collectively, our data highlight disruption of the MFN2–PERK axis-mediated ER–mitochondrion connection as a cause of aging-induced parotid gland dysfunction.
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