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The mitochondria have an important role in modulating cell cycle progression, cell survival, and apoptosis. In the adult heart, the cardiac mitochondria have a unique spatial arrangement and occupy nearly one-third the volume of a cardiomyocyte, being highly efficient for converting the products of glucose or fatty acid metabolism into adenosine triphosphate (ATP). In cardiomyocytes, the decline of mitochondrial function reduces ATP generation and increases the production of reactive oxygen species, which generates impaired heart function. This is because mitochondria play a key role in maintaining cytosolic calcium concentration and modulation of muscle contraction, as ATP is required to dissociate actin from myosin. Beyond that, mitochondria have a significant role in cardiomyocyte apoptosis because it is evident that patients who have cardiovascular diseases (CVDs) have increased mitochondrial DNA damage to the heart and aorta. Many studies have shown that natural products have mitochondria-modulating effects in cardiac diseases, determining them as potential candidates for new medicines. This review outlines the leading plant secondary metabolites and natural compounds derived from microorganisms as modulators of mitochondrial dysfunctions associated with CVDs. [ABSTRACT FROM AUTHOR]