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

Figures

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  Fig. 1. Myocardial structural changes in different cardiomyopathies. A. Healthy heart: The cardiac chamber size, ventricular wall thickness, and myocardial structure are normal. B. HCM: Characterised by asymmetric myocardial hypertrophy (especially in the ventricular septum), ventricular lumen narrowing, and impaired diastolic function. C. DCM: The walls of enlarged chambers become significantly thinner, with reduced myocardial contractility. D. RCM: The ventricular cavity is normal or slightly reduced, and stiff ventricular walls lead to diastolic dysfunction. Created with BioRender.com.

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  Fig. 2. Organelle dysfunction in primary cardiomyopathy. Genetic defects damage organelles through multiple signalling pathways and pathological processes that converge on cardiomyocyte death and dysfunction (HCM, DCM, RCM). A. Mitochondria. An imbalance between reactive oxygen species (ROS) and antioxidant systems drives a self-amplifying vicious cycle involving mtDNA damage, respiratory-chain defects and impaired mitophagy. B. ER/SR. In the cardiac-specialized sarcoplasmic reticulum (SR), t-tubular depolarization opens Cav1.2 channels; Ca2+ influx triggers Ca2+-induced Ca2+ release through RyR2 within local microdomains (couplons) (a, CICR/EC coupling → contraction), while SERCA2a—tonically inhibited by phospholamban (PLN) until PLN phosphorylation (b) —mediates Ca2+ reuptake and relaxation (c). STIM1–ORAI1 mediates store-operated Ca2+ entry (SOCE). In the generic ER compartment, lipid synthesis and protein quality control (chaperones/ERAD) operate alongside the unfolded protein response through three branches: IRE1–XBP1, PERK–eIF2α–CHOP, and ATF6–ATF6f (the ATF6 arm acting adaptively/protectively). The SR is coupled to mitochondria at MAMs (Ca2+/ROS exchange; see Fig. 4). C.…

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  Fig. 3. Mechanism schematic of LMNA mutation causing DCM. In cardiomyocytes with LMNA mutations, increased ERK1/2 activity phosphorylates cofilin-1 at threonine 25. Phosphorylated cofilin-1 inhibits the MRTF-A/SRF signalling pathway, which reduces α-tubulin acetyltransferase 1 (α-TAT1) and thereby decreases acetylation of α-tubulin (Acetyl-α-tubulin K40). This cascade, involving Cdc42, causes the relocalization of connexin 43 (Cx43). Under normal circumstances, Cx43 is almost entirely located in the intercalated disc. However, when the LMNA gene mutates in cardiomyocytes, a series of cascade reactions cause Cx43 to be translocated from the intercalated disc to the lateral wall. Created with BioRender.com.

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  Fig. 4. Ca2+ is transferred from ER to mitochondria via MAMs. ER stress increases ATAD3A activity and prompts its translocation from the mitochondria to the MAM region. ATAD3A then interacts directly with IP3R1 through its N-terminal domain, thereby functionally engageing with IP3R1-GRP75-VDAC1 complex. This interaction markedly increases the amount of Ca2+ released from the ER through IP3R1 into the mitochondria and can even cause mitochondrial calcium overload. In addition, other proteins such as the VAPB–PTPIP51 complex, MFN1/MFN2 (heterodimers) and MFN2 homodimers, DRP1, FUNDC1, and Sig-1R play important roles in exerting MAM function and maintaining its structural stability. The IP3R1–GRP75–VDAC1 and ATAD3A findings depicted here were obtained in diabetic atrial remodelling and in non-cardiac/neurodegenerative models; their operation in primary cardiomyopathy remains to be demonstrated. Created with BioRender.com.