Organelle network dysfunction in primary cardiomyopathy: An integrated perspective on pathogenesis and therapeutics

Primary (genetic) cardiomyopathy comprises a heterogeneous group of predominantly monogenic (genetically determined) myocardial diseases-principally hypertrophic (HCM), dilated (DCM) and restrictive (RCM) phenotypes-and must be distinguished from secondary/acquired cardiomyopathies attributable to ischaemia, valvular disease, pressure overload, diabetes, infection or toxins. This review is restricted to primary cardiomyopathy; because organelle biology has been characterised far more extensively in secondary or acquired settings, evidence derived from such models (ischaemia-reperfusion, pressure overload, diabetes, sepsis, drug toxicity, neurodegenerative or non-cardiac injury models) is explicitly identified as such and treated as indirect, hypothesis-generating support rather than as direct evidence in primary cardiomyopathy. The pathophysiology of primary cardiomyopathy is tightly related to abnormal energy metabolism, protein homeostasis and calcium homeostasis. An increasing body of evidence suggests that organelle malfunction and abnormal inter-organelle interactions play a role in primary cardiomyopathy development. This review focuses on key organelles: mitochondrial dysfunction results in energy deprivation and oxidative imbalance; endoplasmic reticulum stress (ERS) impairs protein folding and calcium homeostasis; defects in the lysosome-mediated autophagy pathway exacerbate the accumulation of intracellular damaged material; Golgi fragmentation affects protein processing and trafficking; and cytoskeletal disruption compromises the structural integrity of myocardium. Furthermore, organelles create complex regulatory networks via structures like mitochondrial-associated ER membranes (MAMs), where imbalances such as aberrant calcium signalling and stress pathway cross-activation exacerbate pathological damage. While previous studies focus on individual proteins or organelles, the heart's high energy consumption and synchronized contraction require understanding cardiomyocytes as a dynamic, interdependent organelle ecosystem. Treating primary cardiomyopathy as a 'organelle network disease', in which organelles constitute a dynamic, interdependent ecosystem, provides a useful integrative paradigm for comprehending the causes. This review lays the groundwork for targeted therapy in primary cardiomyopathy by clarifying the functions of organelles.