Malfunctioning mitochondria strongly participate in the pathogenesis of cardiovascular damage associated with hypertension, and other disease conditions. Eukaryotic cells move, assume their shape, resist mechanical stress, accommodate their internal constituents, and transmit signals by relying on the constant remodeling of cytoskeleton filaments. Mitochondrial ATP is needed to support cytoskeletal dynamics. Conversely, mitochondria need to interact with cytoskeletal elements to achieve normal motility, morphology, localization and function. Extracellular matrix (ECM) quantity and quality influences cellular growth, differentiation, morphology, survival, and mobility. Mitochondria can sense ECM composition changes, and changes in mitochondrial functioning modify the ECM. Maladaptive ECM and cytoskeletal alterations occur in a number of cardiac conditions and in most types of glomerulosclerosis, leading to cardiovascular and renal fibrosis, respectively. Angiotensin-II (Ang-II) -a vasoactive peptide and growth factor- stimulates cytosolic and mitochondrial oxidant production, eventually leading to mitochondrial dysfunction. Also, by inducing integrin/focal adhesion changes, Ang-II regulates ECM and cytoskeletal composition and organization and accordingly contributes to the pathogenesis of cardiovascular remodeling. Ang-II-initiated integrin signalling results in the release of TGF-1, a cytokine that modifies ECM composition and structure, induces reorganization of the cytoskeleton, and modifies mitochondrial function. Therefore, it is possible to hypothesize that the depression of mitochondrial energy metabolism brought about by Ang-II is preceded by Ang-II-induced integrin signaling and the consequent derangement of the cytoskeletal filament network and/or ECM organization. Ang-II-dependent TGF-1 release is a potential link between Ang-II, ECM and cytoskeleton derangements and mitochondrial dysfunction.