Biology subjects

Accornero, F.

Publications and source records attributed to Accornero, F..

4 recordsLinked to original sources

bioRxiv2026

A new tool for quantifying mitochondrial RNA processing intermediates reveals increased levels of immature mRNA species under oxidative stress

Mitochondrial gene expression in mammals requires the processing of polycistronic transcripts into mature RNAs, generating multigene maturation intermediates. Yet these species and their potential association with mitochondrial stress remain poorly characterized. We analyzed intact RNA species in healthy mouse hearts using direct RNA sequencing and identified polyadenylated mitochondrial transcripts containing complete mRNA sequences with uncleaved tRNA extensions, which we termed immature mRNAs (imRNAs). Guided by these findings, we developed a new computational tool to estimate imRNA levels using conventional short-read RNA-seq datasets. Analysis of mouse hearts deficient in mitochondrial superoxide dismutase 2 (SOD2), a model of mitochondrial oxidative stress, revealed selectively elevated levels of imRNAs retaining 5' tRNA extensions, without increases in those with 3' tRNA extensions. Comparative analyses of several mouse models with defects in mitochondrial respiration, transcription, translation, or proteostasis did not reproduce this pattern. In fact, a mouse model of mitochondrial import stress with reduced ROS generation exhibited decreased levels of imRNAs retaining 5' tRNA extensions. Conversely, human induced pluripotent stem cells treated with rotenone, which elevates mitochondrial ROS, showed increased levels of imRNAs retaining 5' but not 3' tRNA extensions, reproducing the pattern observed in SOD2-deficient mouse hearts. These findings identify an imRNA signature potentially associated with mitochondrial oxidative stress. The presence of imRNAs described here suggests that widely used transcriptome analysis pipelines may count these species as mature mRNAs, overestimating mitochondrial mRNA levels and overlooking defects in RNA maturation. By enabling retrospective analysis of processing intermediates, our tool provides access to previously unexamined information in existing RNA-seq datasets.

molecular biology↗

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↗

bioRxiv2021

Influenza virus replication in cardiomyocytes drives heart dysfunction and fibrosis

Cardiac dysfunction is a common extrapulmonary complication of severe influenza virus infection. Prevailing models propose that influenza-associated heart dysfunction is indirectly triggered by cytokine mediated cardiotoxicity downstream of the inflamed lung, rather than by direct infection of cardiac tissue. To test the etiology of cardiac dysfunction resulting from influenza virus infection, we generated a novel recombinant H1N1 influenza A virus that was attenuated in cardiomyocytes by incorporation of target sequences for miRNAs expressed specifically in that cell type (miR133b and miR206). Compared with control virus, mice infected with the miR-targeted virus had significantly reduced heart viral titers, confirming cardiac attenuation of viral replication. The miR-targeted virus, however, was fully replicative and inflammatory in lungs when compared to control virus, and induced similar systemic weight loss. The miR-targeted virus induced considerably lower levels of cardiac arrhythmia, fibrosis, and inflammation, compared with control virus, in mice lacking interferon induced transmembrane protein 3 (IFITM3), which serve as the only available model for severe influenza-associated cardiac pathology. We conclude that robust replication of virus in the heart is required for pathology even when lung inflammation is severe. Indeed, we show that human stem cell-derived cardiomyocytes are susceptible to influenza virus infection. This work establishes a fundamental new paradigm in which influenza virus damages the heart through direct infection of cardiomyocytes.

immunology↗

bioRxiv2019

IFITM3 protects the heart during influenza virus infection

Influenza virus primarily targets the lungs, but dissemination and damage to heart tissue is also known to occur in severe infections. Despite this knowledge, influenza virus-induced cardiac pathogenesis and its underlying mechanisms have been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding interferon-induced transmembrane protein 3 (IFITM3), an antiviral restriction factor, are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to other aspects of pathogenesis, including cardiac dysfunction, is unknown. We now show that IFITM3 deficiency in a newly generated knockout (KO) mouse model exacerbates illness and mortality following influenza A virus infection. Enhanced pathogenesis correlated with increased replication of virus in the lungs, spleens, and hearts of KO mice relative to wildtype (WT) mice. IFITM3 KO mice exhibited normal cardiac function at baseline, but developed severely aberrant electrical activity upon infection, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals. In contrast, WT mice exhibited a mild decrease in heart rate without irregularity of RR intervals. Heightened cardiac virus titers and electrical dysfunction in KO animals was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Our findings reveal an essential role for IFITM3 in controlling influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model to study virus-induced cardiac dysfunction.

immunology↗