Modulation of the matrix redox signaling by mitochondrial Ca~(2+)

Mitochondria sense,shape and integrate signals,and thus function as central players in cellular signal transduction. Ca2+ waves and redox reactions are two such intracellular signals modulated by mitochondria. Mitochondrial Ca2+ transport is of utmost physio-pathological relevance with a strong impact on metabolism and cell fate. Despite its importance,the molecular nature of the proteins involvedin mitochondrial Ca2+ transport has been revealed only recently. Mitochondrial Ca2+ promotes energy metabolism through the activation of matrix dehydrogenases and downstream stimulation of the respiratory chain. These changes also alter the mitochondrial NAD(P)H/NAD(P)+ ratio,but at the same time will increase reactive oxygen species(ROS) production. Reducing equivalents and ROS are having opposite effects on the mitochondrial redox state,which are hard to dissect. With the recent development of genetically encoded mitochondrial-targeted redoxsensitive sensors,real-time monitoring of matrix thiol redox dynamics has become possible. The discoveries of the molecular nature of mitochondrial transporters of Ca2+ combined with the utilization of the novel redox sensors is shedding light on the complex relation between mitochondrial Ca2+ and redox signals and their impact on cell function. In this review,we describe mitochondrial Ca2+ handling,focusing on a number of newly identified proteins involved in mitochondrial Ca2+ uptake and release. We further discuss our recent findings,revealing how mitochondrial Ca2+ influences the matrix redox state. As a result,mitochondrial Ca2+ is able to modulate the many mitochondrial redox-regulated processes linked to normal physiology and disease.     

Control by Ca2+ of mitochondrial structure and function in pancreatic β-cells

Mitochondria play a central role in glucose metabolism and the stimulation of insulin secretion from pancreatic β-cells. In this review, we discuss firstly the regulation and roles of mitochondrial Ca²⁺ transport in glucose-regulated insulin secretion, and the molecular machinery involved. Next, we discuss the evidence that mitochondrial dysfunction in β-cells is associated with type 2 diabetes, from a genetic, functional and structural point of view, and then the possibility that these changes may in part be mediated by dysregulation of cytosolic Ca²⁺. Finally, we review the importance of preserved mitochondrial structure and dynamics for mitochondrial gene expression and their possible relevance to the pathogenesis of type 2 diabetes.     

Mitochondrial metabolism regulates macrophage biology

Mitochondria are critical for regulation of the activation, differentiation, and survival of macrophages and other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes to mitochondrial metabolism and physiology could underlie the corresponding state of macrophage activation. These changes include alterations of oxidative metabolism, mitochondrial membrane potential, and tricarboxylic acid (TCA) cycling, as well as the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) and transformation of the mitochondrial ultrastructure. Here, we provide an updated review of how changes in mitochondrial metabolism and various metabolites such as fumarate, succinate, and itaconate coordinate to guide macrophage activation to distinct cellular states, thus clarifying the vital link between mitochondria metabolism and immunity. We also discuss how in disease settings, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response. Therefore, mitochondria are a vital source of dynamic signals that regulate macrophage biology to fine-tune immune responses.     

Are sirtuin deacylase enzymes important modulators of mitochondrial energy metabolism?

Background

In recent years, reversible lysine acylation of proteins has emerged as a major post-translational modification across the cell, and importantly has been shown to regulate many proteins in mitochondria. One key family of deacylase enzymes is the sirtuins, of which SIRT3, SIRT4, and SIRT5 are localised to the mitochondria and regulate acyl modifications in this organelle.

Scope of review

In this review we discuss the emerging role of lysine acylation in the mitochondrion and summarise the evidence that proposes mitochondrial sirtuins are important players in the modulation of mitochondrial energy metabolism in response to external nutrient cues, via their action as lysine deacylases. We also highlight some key areas of mitochondrial sirtuin biology where future research efforts are required.

Major conclusions

Lysine deacetylation appears to play some role in regulating mitochondrial metabolism. Recent discoveries of new enzymatic capabilities of mitochondrial sirtuins, including desuccinylation and demalonylation activities, as well as an increasing list of novel protein substrates have identified many new questions regarding the role of mitochondrial sirtuins in the regulation of energy metabolism.

General significance

Dynamic changes in the regulation of mitochondrial metabolism may have far-reaching consequences for many diseases, and despite promising initial findings in knockout animals and cell models, the role of the mitochondrial sirtuins requires further exploration in this context. This article is part of a Special Issue entitled Frontiers of mitochondrial research.     

Comparative biochemistry and physiology in Brazil: a critical appraisal

Brazil stood out as the country with the highest number of submissions to the editorial project dedicated to Latin America by the journal Comparative Biochemistry and Physiology. Therefore, we felt that it was important to critically discuss the state of comparative biochemistry and physiology in this country. Our study is based on data collected from the ISI Web-of-Science. We analyzed publication trends through time, availability of novel approaches and techniques, patterns of collaboration among different geographical regions, patterns of collaboration with researchers abroad, and relative efforts dedicated to the study of biochemical and physiological adaptation of native fauna representing different terrestrial Brazilian biomes. Overall, our data shows that comparative biochemistry and physiology is a lively and productive discipline, but that some biases limit the scope of the field in Brazil. Some important limitations are the very heterogeneous distribution of research nuclei throughout the country and the absence of some important approaches, such as remote sensing and the use of molecular biology techniques in a comparative or evolutionary context. We also noticed that international collaboration far surpasses interregional collaboration, and discuss the possible causes and consequences of this situation. Finally, we found that Brazilian comparative biochemistry and physiology is biome-biased, as the Amazonian fauna has received far more attention than the whole pool of fauna representing other terrestrial biomes. We discuss the possible causes of these biases, and propose some directions that may contribute to invigorate the field in the country.     

Control of mitochondria dynamics and oxidative metabolism by cAMP, AKAPs and the proteasome

Mitochondria are highly specialized organelles and major players in fundamental aspects of cell physiology. In yeast, energy metabolism and coupling of mitochondrial activity to growth and survival is controlled by the protein kinase A pathway. In higher eukaryotes, modulation of the so-called A-kinase anchor protein (AKAP) complex regulates mitochondrial dynamics and activity, adapting the oxidative machinery and the metabolic pathway to changes in physiological demand. Protein kinases and phosphatases are assembled by AKAPs within transduction units, providing a mechanism to control signaling events at mitochondria and other target organelles. Ubiquitin-mediated proteolysis of signal transducers and effectors provides an additional layer of complexity in the regulation of mitochondria homeostasis. Genetic evidence indicates that alteration of one or more components of these biochemical pathways leads to mitochondrial dysfunction and human diseases. In this review, we focus on the emerging role of AKAP scaffolds and the proteasome pathway in the control of oxidative metabolism, organelle dynamics and the mitochondrial signaling network. These aspects are crucial elements for maintaining a proper energy balance and cellular lifespan.     

After half a century mitochondrial calcium in- and efflux machineries reveal themselves

Mitochondrial Ca(2+) uptake and release play a fundamental role in the control of different physiological processes, such as cytoplasmic Ca(2+) signalling, ATP production and hormone metabolism, while dysregulation of mitochondrial Ca(2+) handling triggers the cascade of events that lead to cell death. The basic mechanisms of mitochondrial Ca(2+) homeostasis have been firmly established for decades, but the molecular identities of the channels and transporters responsible for Ca(2+) uptake and release have remained mysterious until very recently. Here, we briefly review the main findings that have led to our present understanding of mitochondrial Ca(2+) homeostasis and its integration in cell physiology. We will then discuss the recent work that has unravelled the biochemical identity of three key molecules: NCLX, the mitochondrial Na(+)/Ca(2+) antiporter, MCU, the pore-forming subunit of the mitochondrial Ca(2+) uptake channel, and MICU1, one of its regulatory subunits.     

Modelling mitochondrial dysfunction in mice

Understanding mitochondrial role in normal physiology and pathological conditions has proven to be of high importance as mitochondrial dysfunction is connected with a number of disorders as well as some of the most common diseases (e.g. diabetes or Parkinson's disease). Modeling mitochondrial dysfunction has been difficult mainly due to unique features of mitochondrial genetics. Here we discuss some of the most important mouse models generated so far and lessons learned from them.     

The mammalian circadian timing system: from gene expression to physiology

Many physiological processes in organisms from bacteria to man are rhythmic, and some of these are controlled by self-sustained oscillators that persist in the absence of external time cues. Circadian clocks are perhaps the best characterized biological oscillators and they exist in virtually all light-sensitive organisms. In mammals, they influence nearly all aspects of physiology and behavior, including sleep-wake cycles, cardiovascular activity, endocrinology, body temperature, renal activity, physiology of the gastro-intestinal tract, and hepatic metabolism. The master pacemaker is located in the suprachiasmatic nuclei, two small groups of neurons in the ventral part of the hypothalamus. However, most peripheral body cells contain self-sustained circadian oscillators with a molecular makeup similar to that of SCN (suprachiasmatic nucleus) neurons. This organization implies that the SCN must synchronize countless subsidiary oscillators in peripheral tissues, in order to coordinate cyclic physiology. In this review, we will discuss some recent studies on the structure and putative functions of the mammalian circadian timing system, but we will also point out some apparent inconsistencies in the currently publicized model for rhythm generation.     

Detection and manipulation of mitochondrial reactive oxygen species in mammalian cells

Reactive oxygen species (ROS) are formed upon incomplete reduction of molecular oxygen (O₂) as an inevitable consequence of mitochondrial metabolism. Because ROS can damage biomolecules, cells contain elaborate antioxidant defense systems to prevent oxidative stress. In addition to their damaging effect, ROS can also operate as intracellular signaling molecules. Given the fact that mitochondrial ROS appear to be only generated at specific sites and that particular ROS species display a unique chemistry and have specific molecular targets, mitochondria-derived ROS might constitute local regulatory signals. The latter would allow individual mitochondria to auto-regulate their metabolism, shape and motility, enabling them to respond autonomously to the metabolic requirements of the cell. In this review we first summarize how mitochondrial ROS can be generated and removed in the living cell. Then we discuss experimental strategies for (local) detection of ROS by combining chemical or proteinaceous reporter molecules with quantitative live cell microscopy. Finally, approaches involving targeted pro- and antioxidants are presented, which allow the local manipulation of ROS levels.     

Connecting salt stress signalling pathways with salinity‐induced changes in mitochondrial metabolic processes in C3 plants

Salinity exerts a severe detrimental effect on crop yields globally. Growth of plants in saline soils results in physiological stress, which disrupts the essential biochemical processes of respiration, photosynthesis, and transpiration. Understanding the molecular responses of plants exposed to salinity stress can inform future strategies to reduce agricultural losses due to salinity; however, it is imperative that signalling and functional response processes are connected to tailor these strategies. Previous research has revealed the important role that plant mitochondria play in the salinity response of plants. Review of this literature shows that 2 biochemical processes required for respiratory function are affected under salinity stress: the tricarboxylic acid cycle and the transport of metabolites across the inner mitochondrial membrane. However, the mechanisms by which components of these processes are affected or react to salinity stress are still far from understood. Here, we examine recent findings on the signal transduction pathways that lead to adaptive responses of plants to salinity and discuss how they can be involved in and be affected by modulation of the machinery of energy metabolism with attention to the role of the tricarboxylic acid cycle enzymes and mitochondrial membrane transporters in this process.     

Structure,function, and regulation of mitofusin‐2 in health and disease

Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin‐related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non‐neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression.     

Targeting antioxidants to mitochondria: a new therapeutic direction

Mitochondria play an important role in controlling the life and death of a cell. Consequently, mitochondrial dysfunction leads to a range of human diseases such as ischemia-reperfusion injury, sepsis, and diabetes. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not fully elucidated yet, the oxidative stress appears to be critical. Accordingly, strategies are being developed for the targeted delivery of antioxidants to mitochondria. In this review, we shall briefly discuss cellular reactive oxygen species metabolism and its role in pathophysiology; the currently existing antioxidants and possible reasons why they are not effective in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondrially targeted antioxidants and their future promise for disease treatment.     

Mitochondrial calcium uniporter complex modulation in cancerogenesis

Aberrations in mitochondrial Ca²⁺ homeostasis have been associated with different pathological conditions, including neurological defects, cardiovascular diseases, and, in the last years, cancer. With the recent molecular identification of the mitochondrial calcium uniporter (MCU) complex, the channel that allows Ca²⁺ accumulation into the mitochondrial matrix, alterations in the expression levels or functioning in one or more MCU complex members have been linked to different cancers and cancer-related phenotypes. In this review, we will analyze the role of the uniporter and mitochondrial Ca²⁺ derangements in modulating cancer cell sensitivity to death, invasiveness, and migratory capacity, as well as cancer progression in vivo. We will also discuss some critical points and contradictory results to highlight the consequence of MCU complex modulation in tumor development.