The spatio-temporal organization of mitochondria in cardiac myocytes facilitates myocyte-wide, cluster-bound, mitochondrial inner membrane potential oscillatory depolarizations, commonly triggered by metabolic or oxidative stressors. Local intermitochondrial coupling can be mediated by reactive oxygen species (ROS) that activate inner membrane pores to initiate a ROS-induced-ROS-release process that produces synchronized limit cycle oscillations of mitochondrial clusters within the whole mitochondrial network. The network’s dynamic organization, structure and function can be assessed by quantifying dynamic local coupling constants and dynamic functional clustering coefficients, both providing information about the network’s response to external stimuli. In addition to its special organization, the mitochondrial network of cardiac myocytes exhibits substrate-sensitive coupling constants and clustering coefficients. The myocyte’s ability to form functional clusters of synchronously oscillating mitochondria is sensitive to conditions such as substrate availability (e.g., glucose, pyruvate, β-hydroxybutyrate), antioxidant status, respiratory chain activity, or history of oxidative challenge (e.g., ischemia-reperfusion). This underscores the relevance of quantitative methods to characterize the network’s functional status as a way to assess the myocyte’s resilience to pathological stressors.