Journal of molecular and cellular cardiology最新文献

The human heart has often been described as the "metronome of life" beating continuously over 2.5 billion times across the average lifespan and consuming more than 6 kg of ATP daily. And, during both a healthy and diseased state, the heart predominately relies on the oxidation of fatty acids to fuel its contractile burden of supporting all other organ systems. While metabolic alterations and substrate utilization inflexibility have been well studied and are considered hallmarks of heart failure pathogenesis, the overwhelming majority of these investigations have focused on the health and function of the mitochondria in cardiac myocytes; for good reason given the mitochondria is the location of oxidative phosphorylation complexes that, although debated, can form respiratory super complexes to generate ATP in conjunction with the electron transport chain and TCA cycle. However, there exists a potentially overlooked supporting organelle crucial for fatty acid oxidation - the peroxisome. In addition to serving as the site of long chain fatty acid breakdown into acyl-CoA for transport into the mitochondria, the peroxisome supports cellular viability and function via several critical mechanisms (e.g. plasmalogen synthesis and reactive oxygen species quenching). Despite this, only recently have published reports started to appreciate the potential significance of peroxisomes in cardiovascular physiology. In this review, we aim to provide a global perspective on peroxisomes to include their lifecycle and function gathered mostly from seminal studies in extracardiac tissues and highlight functional roles for peroxisomes directly in the context of cardiac physiology and pathology from more recent literature.

Proteins are essential elements controlling cellular processes. Their synthesis and assembly are vital to the cell as their defect would have deleterious consequences. A finely tuned conserved biological machinery known as the protein quality control (PQC) is in place to correct the defect. The PQC includes the unfolded protein response (UPR), devoted to recognizing, unfolding and refolding abnormally arranged proteins, and the clearance apparatuses composed of the Ubiquitin Proteasome System (UPS) and the Endoplasmic Reticulum Associated Protein Degradation (ERAD). Abnormally folded proteins accumulate in idiopathic dilated cardiomyopathy (iDCM). In this study we investigated the transcriptional and translational landscapes of the UPR and UPS systems using polymerase chain reaction (PCR) and western blotting (WB) of myocardial tissues from iDCM patients and age, ethnicity and biological sex matched control cases. Our results show an increase of the three main UPR axis at the transcription and translational levels, suggesting an activation/inactivation of all axes, with altered PTM/cleavage/splicing eliciting abnormal downstream function. Notably, aging independently affects this machinery in diseased and control individuals. In addition, mutation in presenilin gene associated with Alzheimer's disease led to post-translational changes of the UPR components suggesting that genetic risk may exacerbate the natural age and disease-driven protein dyshomeostasis. In conclusion, our findings highlight that abnormalities of UPR are a still largely unexplored feature in heart failure to be view in its entirely. The combined alteration of several target proteins of these pathways configures defective proteostasis as a condition of misfolded peptides accumulation ultimately exhausting the cell survival capabilities.