Current Opinion in Physiology最新文献

Most cellular protein synthesis, including synthesis of membrane-targeted and secreted proteins, which are critical for cellular and organ crosstalk, takes place at the endoplasmic reticulum (ER), placing the ER at the nexus of cellular signaling, growth, metabolism, and stress sensing. Ample evidence has established the dysregulation of protein homeostasis and the ER unfolded protein response (UPR) in cardiovascular disease. However, the mechanisms of stress sensing and signaling in the ER are incompletely defined. Recent studies have defined notable functions for the inositol-requiring kinase 1 (IRE1)/X-box- binding protein-1 (XBP1) branch of the UPR in regulation of cardiac function. This review highlights the mechanisms underlying IRE1 activation and the IRE1 interactome, which reveals unexpected functions for the UPR and summarizes our current understanding of the functions of IRE1 in cardiovascular disease.

Post-transcriptional modifications encompass a large group of RNA alterations that control gene expression. Methylation of the N⁶-adenosine (m⁶A) of mRNA is a prevalent modification that alters the life cycle of transcripts. The roles that m⁶A play in regulating cardiac homeostasis and injury response are an active area of investigation, but it is clear that this chemical modification is a critical controller of fibroblast-to-myofibroblast transition, cardiomyocyte hypertrophy and division, and the structure and function of the extracellular matrix. Here, we discuss the latest findings of m⁶A in cardiac muscle and matrix.

Cardiac fibroblasts play critical roles in the maintenance of cardiac structure and the response to cardiac insult. Extracellular matrix deposition by activated resident cardiac fibroblasts, called myofibroblasts, is an essential wound healing response. However, persistent fibroblast activation contributes to pathological fibrosis and cardiac chamber stiffening, which can cause diastolic dysfunction, heart failure, and initiate lethal arrhythmias. The dynamic and phenotypically plastic nature of cardiac fibroblasts is governed in part by the transcriptional regulation of genes encoding extracellular matrix molecules. Understanding how fibroblasts integrate various biomechanical cues into a precise transcriptional response may uncover therapeutic strategies to prevent fibrosis. Here, we provide an overview of the recent literature on transcriptional control of cardiac fibroblast plasticity and fibrosis, with a focus on canonical and noncanonical transforming growth factor beta signaling, biomechanical regulation of Hippo/yes-associated protein and Rho/myocardin-related transcription factor signaling, and metabolic and epigenetic control of fibroblast activation.

Interstitial cardiac fibrosis arises due to deposition and accumulation of extracellular matrix (ECM) and occurs in hearts subject to increases in mechanical load. Cardiac fibroblasts sense changes in mechanical load through several mechanosensors including integrin ECM receptors and stretch activated ion channels, which signal to induce ECM protein production through various pathways. Over time, processes intrinsic to fibroblasts and to the ECM occur to progress and sustain fibrosis through reciprocal, positive feedback loops. Changes in ECM include nascent collagen production, changes in ECM composition, and differential modification of collagen in fibers. Persistently fibrotic ECM contributes to a stiffer myocardium which can lead to the development of cardiomyopathies and heart failure.

Mitochondrial dysfunction has been reported in monogenic phenotypes, but also as part of common complex disorders. Explanations for the underlying mechanism of both disease types mostly focused on mutations in the open-reading frames of proteins encoded by either the mitochondrial or nuclear genomes, as well as in tRNA or ribosomal RNA genes in the mitochondrial DNA (mtDNA). Although disease-causing mutations have been identified in regulatory proteins of mtDNA replication and maintenance, coordination between the regulation of mitochondrial and nuclear gene expression was only rarely considered as an explanation for mitochondrial dysfunction in diseases. Here, we review evidence suggesting that compromised coordination of mitonuclear regulation of gene expression constitutes an attractive mechanism to explain the involvement of mitochondrial dysfunction in a variety of disorders and in evolutionary processes. We discuss candidate mechanisms for coordination of mitonuclear gene expression and future avenues for their identification, with emphasis on functional genomics techniques.

How mitochondria alter their morphology to meet cellular demands epitomizes the ‘form follows function’ architectural principle. These remodeling events are collectively termed ‘mitochondrial dynamics’. The influence of mitochondrial dynamics and of the mitochondria-shaping proteins that control it on skeletal muscle physiology has become clearer. Endurance exercise prompts mitochondrial morphological changes that augment the respiratory capacity of the worked muscles. Mechanistically, exercise training increases mitochondrial fusion protein levels in skeletal muscle to promote the development of a hyperfused mitochondrial network that possesses denser cristae. Conversely, disruptions to the mitochondrial network through imbalances in mitochondrial dynamics lead to muscle atrophy. Insight into the connection between mitochondrial morphology and muscle-mass maintenance will help to pinpoint therapeutic targets that can be exploited to counteract sarcopenia and muscle atrophy in pathological conditions.

The remodeling of cardiac metabolism, such as changes in substrate utilization and mitochondrial dysfunction, has long been suggested to impair myocardial energetics that leads to energy starvation of the failing hearts. However, most of the studies to date focused on heart failure with reduced ejection fraction and the role of metabolism in the development of heart failure with preserved ejection fraction (HFpEF) is thus not well defined. Studies of cardiac metabolism in HFpEF are emerging with the recent progress in animal models. This review seeks to provide an overview of metabolic profile in HFpEF hearts from available reports and to highlight future research directions.

Disruptions in oxidative metabolism are often accompanied by tissue accumulation of catabolic carbon intermediates, including acyl CoA molecules that can react with the epsilon amino group of lysine residues on cellular proteins. In general, acyl-lysine post-translational modifications (PTMs) on mitochondrial proteins correlate negatively with energy homeostasis and are offset by the mitochondrial sirtuins, a prominent family of NAD⁺-dependent deacylases linked favorably to longevity and metabolic resilience. Whereas studies over the past decade elicited widespread conjecture as to the far-reaching regulatory roles of these PTMs, more recent work has stirred controversy in this field of study. This review draws attention to discrepancies in the science, challenges current dogma, and encourages new perspectives on the physiological relevance of mitochondrial lysine acylation.

Mitochondrial function is fundamental to maintaining metabolic homeostasis. Alterations in mitochondrial biogenesis, energy production, and dynamics are behind many metabolic diseases affecting particularly the muscular and nervous systems. Therefore, synchronized coordination between organelles is required to sustain homeostasis. The integrated stress response (ISR) is a heavily investigated pathway that allows for communication between organelles, including the mitochondria and the nucleus among others. The ISR slows down protein synthesis in the cytoplasm and modifies the transcriptome in the nucleus following mitochondrial stress. With the help of the ATF4 transcription factor, it promotes metabolic rewiring, amino acid, and antioxidant synthesis to counteract cellular stress. Under chronic stress, the ISR leads to apoptotic cell death. However, the mechanisms as to how the ISR can coordinate cell death and survival depending on the type of insult remain unclear. In this review, we will discuss the mechanisms of activation of the ISR under different mitochondrial dysfunctions. We propose a few mechanisms and factors that contribute to the cell-specific response. Finally, we discuss the role of the ISR in neurodegenerative diseases given the important implications of the mitochondria in maintaining healthy neurological function.

Ischemia-reperfusion injury can occur in a variety of organs resulting in deleterious effects that significantly compromise cellular function and viability. Mitochondria have been shown to play a major role in the consequential endpoints resulting from ischemia and reperfusion injury. In a series of studies, we have developed a novel therapeutic intervention to ameliorate the effects ischemia-reperfusion injury on mitochondria through organelle transplantation, specifically mitochondrial transplantation. In this mini-review, prepared for a broad audience, the current literature and scope of mitochondrial transplantation in experimental in vitro and animal studies and from a recent clinical study in human pediatric patients are presented.