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Annual Review of Physiology

Maor Sauler, Isabel S Bazan, Patty J Lee
Regulated cell death is a major mechanism to eliminate damaged, infected, or superfluous cells. Previously, apoptosis was thought to be the only regulated cell death mechanism; however, new modalities of caspase-independent regulated cell death have been identified, including necroptosis, pyroptosis, and autophagic cell death. As an understanding of the cellular mechanisms that mediate regulated cell death continues to grow, there is increasing evidence that these pathways are implicated in the pathogenesis of many pulmonary disorders...
November 28, 2018: Annual Review of Physiology
Diane M Ward, Suzanne M Cloonan
Mitochondria are an iconic distinguishing feature of eukaryotic cells. Mitochondria encompass an active organellar network that fuses, divides, and directs a myriad of vital biological functions, including energy metabolism, cell death regulation, and innate immune signaling in different tissues. Another crucial and often underappreciated function of these dynamic organelles is their central role in the metabolism of the most abundant and biologically versatile transition metals in mammalian cells, iron. In recent years, cellular and animal models of mitochondrial iron dysfunction have provided vital information in identifying new proteins that have elucidated the pathways involved in mitochondrial homeostasis and iron metabolism...
November 28, 2018: Annual Review of Physiology
Michael Neinast, Danielle Murashige, Zoltan Arany
Branched chain amino acids (BCAAs) are building blocks for all life forms. We review here the fundamentals of BCAA metabolism in mammalian physiology. Decades of studies have elicited a deep understanding of biochemical reactions involved in BCAA catabolism. In addition, BCAAs and various catabolic products act as signaling molecules, activating programs ranging from protein synthesis to insulin secretion. How these processes are integrated at an organismal level is less clear. Inborn errors of metabolism highlight the importance of organismal regulation of BCAA physiology...
November 28, 2018: Annual Review of Physiology
Gang Liu, Ross Summer
The lung is often overlooked as a metabolically active organ, yet biochemical studies have long demonstrated that glucose utilization surpasses that of many other organs, including the heart, kidney, and brain. For most cells in the lung, energy consumption is relegated to performing common cellular tasks, like mRNA transcription and protein translation. However, certain lung cell populations engage in more specialized types of energy-consuming behaviors, such as the beating of cilia or the production of surfactant...
November 28, 2018: Annual Review of Physiology
Yaqing Zhang, Howard C Crawford, Marina Pasca di Magliano
Pancreatic cancer is characterized by an extensive fibroinflammatory reaction that includes immune cells, fibroblasts, extracellular matrix, vascular and lymphatic vessels, and nerves. Overwhelming evidence indicates that the pancreatic cancer microenvironment regulates cancer initiation, progression, and maintenance. Pancreatic cancer treatment has progressed little over the past several decades, and the prognosis remains one of the worst for any cancer. The contribution of the microenvironment to carcinogenesis is a key area of research, offering new potential targets for treating the disease...
November 12, 2018: Annual Review of Physiology
Haguy Wolfenson, Bo Yang, Michael P Sheetz
It is increasingly clear that mechanotransduction pathways play important roles in regulating fundamental cellular functions. Of the basic mechanical functions, the determination of cellular morphology is critical. Cells typically use many mechanosensitive steps and different cell states to achieve a polarized shape through repeated testing of the microenvironment. Indeed, morphology is determined by the microenvironment through periodic activation of motility, mechanotesting, and mechanoresponse functions by hormones, internal clocks, and receptor tyrosine kinases...
November 7, 2018: Annual Review of Physiology
Sabine Schneider, Christina M Wright, Robert O Heuckeroth
At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system...
October 31, 2018: Annual Review of Physiology
Bo Wang, Peter Tontonoz
Phospholipids are major constituents of biological membranes. The fatty acyl chain composition of phospholipids determines the biophysical properties of membranes and thereby affects their impact on biological processes. The composition of fatty acyl chains is also actively regulated through a deacylation and reacylation pathway called Lands' cycle. Recent studies of mouse genetic models have demonstrated that lysophosphatidylcholine acyltransferases (LPCATs), which catalyze the incorporation of fatty acyl chains into the sn-2 site of phosphatidylcholine, play important roles in pathophysiology...
October 31, 2018: Annual Review of Physiology
Luke Grundy, Andelain Erickson, Stuart M Brierley
Most of us live blissfully unaware of the orchestrated function that our internal organs conduct. When this peace is interrupted, it is often by routine sensations of hunger and urge. However, for >20% of the global population, chronic visceral pain is an unpleasant and often excruciating reminder of the existence of our internal organs. In many cases, there is no obvious underlying pathological cause of the pain. Accordingly, chronic visceral pain is debilitating, reduces the quality of life of sufferers, and has large concomitant socioeconomic costs...
October 31, 2018: Annual Review of Physiology
Miguel Quirós, Asma Nusrat
The gastrointestinal mucosa, structurally formed by the epithelium and lamina propria, serves as a selective barrier that separates luminal contents from the underlying tissues. Gastrointestinal mucosal wound repair is orchestrated by a series of spatial and temporal events that involve the epithelium, recruited immune cells, resident stromal cells, and the microbiota present in the wound bed. Upon injury, repair of the gastrointestinal barrier is mediated by collective migration, proliferation, and subsequent differentiation of epithelial cells...
October 24, 2018: Annual Review of Physiology
Ralf Schmid, Richard J Evans
In the nervous system, ATP is co-stored in vesicles with classical transmitters and released in a regulated manner. ATP from the intracellular compartment can also exit the cell through hemichannels and following shear stress or membrane damage. In the past 30 years, the action of ATP as an extracellular transmitter at cell-surface receptors has evolved from somewhat of a novelty that was treated with skepticism to purinergic transmission being accepted as having widespread important functional roles mediated by ATP-gated ionotropic P2X receptors (P2XRs)...
October 24, 2018: Annual Review of Physiology
Grant B McClelland, Graham R Scott
Comparative physiology studies of high-altitude species provide an exceptional opportunity to understand naturally evolved mechanisms of hypoxia resistance. Aerobic capacity (VO2 max) is a critical performance trait under positive selection in some high-altitude taxa, and several high-altitude natives have evolved to resist the depressive effects of hypoxia on VO2 max. This is associated with enhanced flux capacity through the O2 transport cascade and attenuation of the maladaptive responses to chronic hypoxia that can impair O2 transport...
September 26, 2018: Annual Review of Physiology
S F Morrison, K Nakamura
Maintenance of a homeostatic body core temperature is a critical brain function accomplished by a central neural network. This orchestrates a complex behavioral and autonomic repertoire in response to environmental temperature challenges or declining energy homeostasis and in support of immune responses and many behavioral states. This review summarizes the anatomical, neurotransmitter, and functional relationships within the central neural network that controls the principal thermoeffectors: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for heat production...
September 26, 2018: Annual Review of Physiology
Gerald W Dorn
The concept that mitochondria are highly dynamic is as widely accepted as it is untrue for a number of important contexts. Healthy mitochondria of the most energy-dependent and mitochondrial-rich mammalian organ, the heart, only rarely undergo fusion or fission and are seemingly static within cardiac myocytes. Here, we revisit mitochondrial dynamism with a fresh perspective developed from the recently discovered multifunctionality of mitochondrial fusion proteins and newly defined mechanisms for direct cross talk between mitochondrial dynamics, biogenesis, quality control, and trafficking pathways...
September 26, 2018: Annual Review of Physiology
Friederike Cuello, Philip Eaton
Oxidant molecules are produced in biological systems and historically have been considered causal mediators of damage and disease. While oxidants may contribute to the pathogenesis of disease, evidence continues to emerge that shows these species also play important regulatory roles in health. A major mechanism of oxidant sensing and signaling involves their reaction with reactive cysteine thiols within proteins, inducing oxidative posttranslational modifications that can couple to altered function to enable homeostatic regulation...
September 14, 2018: Annual Review of Physiology
David A Hood, Jonathan M Memme, Ashley N Oliveira, Matthew Triolo
Mitochondria are critical organelles responsible for regulating the metabolic status of skeletal muscle. These organelles exhibit remarkable plasticity by adapting their volume, structure, and function in response to chronic exercise, disuse, aging, and disease. A single bout of exercise initiates signaling to provoke increases in mitochondrial biogenesis, balanced by the onset of organelle turnover carried out by the mitophagy pathway. This accelerated turnover ensures the presence of a high functioning network of mitochondria designed for optimalATPsupply, with the consequence of favoring lipid metabolism, maintaining muscle mass, and reducing apoptotic susceptibility over the longer term...
September 14, 2018: Annual Review of Physiology
Adrian O Olivares, Tania A Baker, Robert T Sauer
AAA+ proteolytic machines use energy from ATP hydrolysis to degrade damaged, misfolded, or unneeded proteins. Protein degradation occurs within a barrel-shaped self-compartmentalized peptidase. Before protein substrates can enter this peptidase, they must be unfolded and then translocated through the axial pore of an AAA+ ring hexamer. An unstructured region of the protein substrate is initially engaged in the axial pore, and conformational changes in the ring, powered by ATP hydrolysis, generate a mechanical force that pulls on and denatures the substrate...
February 10, 2018: Annual Review of Physiology
Viola Vogel
Cells need to be anchored to extracellular matrix (ECM) to survive, yet the role of ECM in guiding developmental processes, tissue homeostasis, and aging has long been underestimated. How ECM orchestrates the deterioration of healthy to pathological tissues, including fibrosis and cancer, also remains poorly understood. Inquiring how alterations in ECM fiber tension might drive these processes is timely, as mechanobiology is a rapidly growing field, and many novel mechanisms behind the mechanical forces that can regulate protein, cell, and tissue functions have recently been deciphered...
February 10, 2018: Annual Review of Physiology
Edward C Eckels, Rafael Tapia-Rojo, Jamie Andrés Rivas-Pardo, Julio M Fernández
Single-molecule atomic force microscopy and magnetic tweezers experiments have demonstrated that titin immunoglobulin (Ig) domains are capable of folding against a pulling force, generating mechanical work that exceeds that produced by a myosin motor. We hypothesize that upon muscle activation, formation of actomyosin cross bridges reduces the force on titin, causing entropic recoil of the titin polymer and triggering the folding of the titin Ig domains. In the physiological force range of 4-15 pN under which titin operates in muscle, the folding contraction of a single Ig domain can generate 200% of the work of entropic recoil and occurs at forces that exceed the maximum stalling force of single myosin motors...
February 10, 2018: Annual Review of Physiology
Lei Li, Wen-Cheng Xiong, Lin Mei
Synapses, the fundamental unit in neuronal circuits, are critical for learning and memory, perception, thinking, and reaction. The neuromuscular junction (NMJ) is a synapse formed between motoneurons and skeletal muscle fibers that is covered by Schwann cells (SCs). It is essential for controlling muscle contraction. NMJ formation requires intimate interactions among motoneurons, muscles, and SCs. Deficits in NMJ formation and maintenance cause neuromuscular disorders, including congenital myasthenic syndrome and myasthenia gravis...
February 10, 2018: Annual Review of Physiology
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