CK2α Deficiency Drives Myocardial Fibrosis via Desmin-Induced Mitochondrial Dysfunction

Myocardial fibrosis, a hallmark of heart failure, is driven by pathological crosstalk between stressed cardiomyocytes and activated fibroblasts, yet the initiating signals from cardiomyocytes remain poorly defined. Here, we identify downregulation of casein kinase 2α (CK2α) in cardiomyocytes as a conserved and early trigger of fibrotic remodeling. Cardiomyocyte-specific CK2α loss induces progressive mitochondrial proteome collapse, metabolic reprogramming, and bioenergetic failure. This mitochondrial impairment induces oxidative stress and sterile inflammation, subsequently activating cardiac fibroblasts via paracrine mediators, such as IL-6, thereby establishing a direct mechanistic link between a cardiomyocyte-intrinsic defect and fibroblast activation. Mechanistically, CK2α preserves mitochondrial-cytoskeletal integrity by directly phosphorylating the intermediate filament Desmin at threonine 452 (Thr452). This phosphorylation recruits the chaperone protein αB-crystallin (Cryab) to prevent pathological Desmin aggregation. Disruption of this quality control checkpoint, suffices to recapitulate the full spectrum of mitochondrial dysfunction and pro-fibrotic signaling. Notably, AAV9-mediated restoration of CK2α specifically in cardiomyocytes preserves mitochondrial structure, rescues bioenergetic function, and attenuates fibrosis. Our findings uncover a CK2α-Desmin-mitochondrial quality control axis as a critical metabolic-structural checkpoint in cardiomyocytes and establish that cardiomyocyte-initiated paracrine signaling drives fibroblast activation, highlighting new therapeutic strategies for fibrotic heart disease.