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Figure 4. Mechanisms involved in the activation of UPRmt in the development of age-associated CVDs. The progression of cardiovascular disease (CVDs) is accompanied by overproduction of ROS, accumulation of unfolded proteins, changes in mitochondrial dynamics, fibrosis, and cardiomyocyte death. UPR^mt, as a response to mitochondrial damage, has emerged as a therapeutic target for the treatment of age-associated CVDs as it modulates the mitochondrial repair and recovery processes. In heart failure (HF), decreased LonP1, HSP70/60/9, and YME1L proteases have been reported to cause the accumulation of misfolded proteins inside the mitochondria and, thus, the activation of UPR^mt. In acute myocardial infarction (AMI), in addition to being characterized by calcium (Ca²⁺) overload, inflammation, and oxidative stress, a decrease in LonP1 has also been observed, which activates UPR^mt through the p-eIF2α-ATF5 pathway, which induces the latter to enter the nucleus. In dilated cardiomyopathy (DCM), decreased mitochondrial NAD-dependent Sirtuin-3/1 deacetylases (SIRT-3 and -1) and HSP60 activate UPR^mt. In the face of this damage, the implementation of strategies (such as exercise and diet) has successfully mitigated UPR^mt by modulating the response of LonP1, YME1L, and SIRT-3 in elderly patients with CVDs. ROS: Reactive oxygen species; LonP1: Lon1 peptidase; HSP: Heat shock protein; YME1L: yeast mitochondrial escape protein type 1; p-eIF2α: phosphorylation of eukaryotic initiation factor 2 alpha; ATF5: transcription factor-5. Created using BioRender (www.app.biorender.com).