Mitochondrial Adaptation to Mechanical Stress in Cardiac Ageing and Disease

Mechanical forces shape the heart's energy factories. This review explores how mitochondria in cardiac cells sense and respond to biomechanical stress, altering their structure, positioning, and metabolism. By linking mechanical cues to mitochondrial adaptation, the article highlights pathways driving heart disease and points to new strategies for preserving cardiac energy balance. Abstract Cardiomyocytes are highly specialized cells that depend on a finely tuned interplay between mechanical forces and metabolic activity to sustain continuous contraction throughout life. While the role of mitochondria in supporting cardiac biomechanics through ATP production, calcium buffering, and redox signaling is well established, the reverse relationship, namely how mechanical forces influence mitochondrial behavior, remains comparatively understudied. This review explores the emerging concept of biomechanical feedback on mitochondrial dynamics in cardiomyocytes. Mechanical cues are shown to regulate mitochondrial morphology, positioning, and function via diverse mechanotransduction pathways. Key mechanisms include integrin signaling, stretch‐activated ion channels, and cytoskeletal networks, alongside mechanical stimuli such as cyclic stretch, pressure overload, and shear stress, which modulate mitochondrial fusion/fission processes, membrane potential, calcium handling, and reactive oxygen species production. The implications of these interactions are considered in the context of cardiac pathologies, including hypertrophy, ischemia‐reperfusion injury, and heart failure. By integrating perspectives from mitochondrial biology and cardiac mechanobiology, this review aims to foster interdisciplinary research and inform novel therapeutic approaches for cardiovascular disease. Mechanical forces shape the heart's energy factories. This review explores how mitochondria in cardiac cells sense and respond to biomechanical stress, altering their structure, positioning, and metabolism. By linking mechanical cues to mitochondrial adaptation, the article highlights pathways driving heart disease and points to new strategies for preserving cardiac energy balance. Abstract Cardiomyocytes are highly specialized cells that depend on a finely tuned interplay between mechanical forces and metabolic activity to sustain continuous contraction throughout life. While the role of mitochondria in supporting cardiac biomechanics through ATP production, calcium buffering, and redox signaling is well established, the reverse relationship, namely how mechanical forces influence mitochondrial behavior, remains comparatively understudied. This review explores the emerging concept of biomechanical feedback on mitochondrial dynamics in cardiomyocytes. Mechanical cues are shown to regulate mitochondrial morphology, positioning, and function via diverse mechanotransduction pathways. Key mechanisms include integrin signaling, stretch-activated ion channels, and cytoskeletal networks, alongside mechanical stimuli such as cyclic stretch, pressure overload, and shear stress, which modulate mitochondrial fusion/fission processes, membrane potential, calcium handling, and reactive oxygen species production. The implications of these interactions are considered in the context of cardiac pathologies, including hypertrophy, ischemia-reperfusion injury, and heart failure. By integrating perspectives from mitochondrial biology and cardiac mechanobiology, this review aims to foster interdisciplinary research and inform novel therapeutic approaches for cardiovascular disease. Advanced Science, EarlyView.