Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart

•Mice with heterozygous knockout of Bag3 are phenotypically normal by echocardiography at 8 to 10 weeks of age but show marked changes in left ventricular function by 18 weeks of age.•Evaluation of the proteome of 8- to 10-week-old Bag3+/– mice revealed abnormalities in proteins associated with metabolism and programmed cell death or apoptosis despite a normal phenotype.•Bag3 regulates cellular apoptosis both through canonical as well as noncanonical pathways.•Bag3 interacts directly with the inhibitor of apoptosis protein 1/2 (cIAP1/2 or cIAP), the mitochondrial import receptor subunit TOM22, and the Ca2+ uniporter in regulating cellular apoptosis and inflammation, mitochondrial metabolism, and the generation of the mitochondrial membrane potential, respectively.•Decreased levels of Bag3 cause a shift from a balance between the intrinsic and extrinsic pathways of caspase activation to signaling that favors activation of caspase-8.•Bag3 is indispensable to the health of a cell because it serves as a molecular glue that maintains key proteins in specific microdomains that are critical for normal physiology in high-functioning cells.