Background: Cardiac fibroblasts (CFs) are essential non-muscle cells in the myocardium, responsible for maintaining the extracellular matrix (ECM) and providing structural support. Following injury, CFs become activated and differentiate into myofibroblasts (myoFbs), a process driven by growth factors, mechanical stress, and cytokines. Mitochondria play a critical role in both CFs and myoFbs, with mitochondrial homeostasis relying on the mitochondrial protein quality control (MPQC) system, which is crucial for cellular adaptation and survival. Hypothesis and Aim: CLPB, a component of the MPQC system in the intermembrane space (IMS), is a chaperonin with disaggregase activity. CLPB expression is reduced in various fibrosis models, including myocardial infarction (MI) and pressure overload-induced heart failure. However, its role in cardiac fibrosis and mitochondrial remodeling during cardiac injury remains unknown. This study aims to investigate the function of CLPB in regulating CFs activation during cardiac injury, providing novel insights into its potential role in cardiac pathology. Methods and Results: 1° human and mouse CF exhibit decreased CLPB levels in response to fibrosis stimuli (TGFβ and Ang II). RNA-seq of Clpb –/– MCFs revealed an increase in pro-fibrotic and a decrease in anti-fibrotic markers, with TGFβ exposure further exacerbating these changes. TGFβ exposure leads to increased SMAD3 phosphorylation and higher α-SMA levels, indicating the activation of fibrotic pathways in Clpb –/– . Additionally, wild-type MCFs exhibited higher OXPHOS capacity in response to TGFβ, while Clpb –/– led to a shift toward glycolytic metabolism, promoting myoFb formation. In a cardiac spheroid model derived from human induced pluripotent stem cells (iPSCs), the loss of CLPB leads to contractile dysfunction, suggesting abnormal cardiac contractility. Conclusion: Our findings demonstrate the role of CLPB in regulating fibroblast activation following cardiac injury, mitochondrial bioenergetics, and fibrosis progression. The loss of CLPB leads to a pro-fibrotic phenotype, metabolic reprogramming, and contractile dysfunction, highlighting its potential as a therapeutic target for attenuating cardiac fibrosis. Understanding CLPB’s role in mitochondrial homeostasis may provide new insights into fibrosis-associated cardiac remodeling and heart failure.
Goyani et al. (Fri,) studied this question.