RationaleMitochondrial (MITO) dysfunction occurs with age in the heart and decreases the tolerance of the aged heart to superimposed cardiac stress. It is unclear how aging leads to MITO dysfunction. The endoplasmic reticulum (ER) is closely connected to MITO via shared membrane domains that mediate ER‐MITO cross‐talk including calcium loading. Induction of ER stress leads to MITO dysfunction in adult hearts. ER stress is increased with aging in the heart.ObjectiveTo study the contribution of ER stress to MITO dysfunction during the progression of cardiac aging.MethodsSubsarcolemmal MITO (SSM) and interfibrillar MITO (IFM) were isolated from 3, 12, 18, and 24 Mon. male C57BL/6 mouse hearts (NIA Colony, Charles River). Oxidative phosphorylation (OXPHOS, nAO/min/mg protein) was measured in isolated MITO. Calcium Retention Capacity (nmol calcium/mg protein) was used to reflect the sensitivity to calcium‐induced mitochondria permeability transition pore opening (MPTP). The contents of CHOP (transcription factor C/EBP homologous protein) and cleaved ATF6 (50 kDa) were used as markers of ER stress.ResultsER stress increased during aging as shown by greater CHOP and cleaved ATF6 contents at 18 Mon. (Figure) whereas OXPHOS remained unchanged (Table). OXPHOS with complex I (glutamate+malate) and complex IV (TMPD+ascorbate) substrates was decreased at 24 Mon. in IFM. OXPHOS in SSM remained unaltered by age (data not shown). Susceptibility to (MPTP) opening was increased at 24 Mon. in IFM.ConclusionAging leads to increased ER stress that occurs before the onset of MITO dysfunction. ER‐IFM crosstalk, likely involving altered Ca+2 dynamics as indicated by increased MPTP susceptibility, is a potential new mechanism of age‐induced MITO defects in the heart. Age‐induced defects in IFM, in turn, exacerbate cardiac injury in response to superimposed cardiac disease, including ischemia‐reperfusion.Support or Funding InformationThis work was supported by the Office of Research and Development, Medical Research Service Merit Review Award (2IO1BX001355‐01A2) and Department of Veterans Affairs (EJL); National Institutes of Health NIH R21AG054975‐01 (QC)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.