Addya, S. | Search bioRxiv

bioRxiv2026

BK Channels Orchestrate Cardiac Homeostasis Through Mitochondrial Uncoupling Proteins

BK channels, coded by the Kcnma1 gene, integrate voltage and intracellular Ca2+ signals and are recognized for their roles in smooth muscle and neuronal excitability. However, their contribution to baseline cardiac physiology remains poorly defined. Here we uncover a fundamental function for BK channels in maintaining normal cardiac performance, independent of pathological stress. Using non-invasive echocardiography, transcriptional profiling, and mechanistic analyses, we demonstrate that Kcnma1 deletion disrupts ventricular function, and remodels metabolic and stress-response pathways. Transcriptomic profiling revealed selective downregulation of mitochondrial uncoupling proteins (UCPs) and suppression of the PGC-1/FOXO3a axis, without broad loss of oxidative phosphorylation components. Enhancing UCP expression restored cardiac performance, indicating that mitochondrial uncoupling and redox control constitute key downstream effectors of BK signaling. Together, these results identify a physiological role for BK channels in maintaining myocardial function and define a mitochondrial BK-UCP axis, critical for cardiac homeostasis.

cell biology↗

bioRxiv2020

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in murine coronavirus-induced neuroinflammation

Mouse hepatitis virus (MHV) belongs to the same beta-coronavirus family as SARS-CoV-2, MERS-CoV, and SARS-CoV. Studies have shown the requirement of host cellular proteases for priming the surface spike protein during viral entry and transmission in coronaviruses. The metzincin family of metal-dependent endopeptidases called matrix metalloproteinases (MMPs) is involved in virus encephalitis, enhanced blood-brain barrier permeability, or cell-to-cell fusion upon viral infection. Here we show the role of MMPs as mediators of virus-induced host neuroinflammatory response in the MHV model. Infection of mice with wild-type MHV-A59 or its isogenic recombinant strains, RSA59 or RSMHV2 significantly upregulated MMP-3, MMP-8, and MMP-14 transcript levels. Functional network assessment with Ingenuity Pathway Analysis revealed a direct involvement of these MMPs in disrupting junctional assembly between endothelial cells via interaction with junctional adhesion molecules and thereby facilitating transmigration of peripheral lymphocytes. Our findings also suggest mRNA upregulation of Park7, which is involved in NADPH oxidase-dependent ROS production, following RSA59 infection. RSA59 infection resulted in elevated mRNA levels of RelA, a subunit of NF-{kappa}B. Infection with MHV-A59 is known to generate ROS, and oxidative stress can activate NF-{kappa}B. Thus, our findings indicate the existence of a possible nexus between ROS, NF-{kappa}B, and MMPs in RSA59-induced neuroinflammation. We also assessed the expression of endogenously produced regulators of MMP activities. Elevated mRNA and protein levels of tissue inhibitors of metalloproteinases 1 (TIMP-1) in MHV-A59 infection are suggestive of a TIMP-1 mediated host antiviral response. ImportanceThe newly emergent coronavirus has brought the world to a near standstill. In the past, studies have focused on the function of host proteases in virus attachment and entry. Our research indicates the involvement of a group of metal-dependent host proteases in inflammation associated with coronavirus infection. Inflammation is the first response of the host to virus infection. While it helps in restricting the spread and clearance of viral particles, uncontrolled inflammation results in several inflammatory consequences. Therefore, it becomes vital to limit unchecked host immune response. The inhibition of specific metalloproteases represents a potential new therapeutic approach in coronavirus infection and disease outcome.

microbiology↗