Understanding mitochondrial complex I assembly in health and disease

Complex I (NADH:ubiquinone oxidoreductase) is the largest multimeric enzyme complex of the mitochondrial respiratory chain, which is responsible for electron transport and the generation of a proton gradient across the mitochondrial inner membrane to drive ATP production. Eukaryotic complex I consists of 14 conserved subunits, which are homologous to the bacterial subunits, and more than 26 accessory subunits. In mammals, complex I consists of 45 subunits, which must be assembled correctly to form the properly functioning mature complex. Complex I dysfunction is the most common oxidative phosphorylation (OXPHOS) disorder in humans and defects in the complex I assembly process are often observed. This assembly process has been difficult to characterize because of its large size, the lack of a high resolution structure for complex I, and its dual control by nuclear and mitochondrial DNA. However, in recent years, some of the atomic structure of the complex has been resolved and new insights into complex I assembly have been generated. Furthermore, a number of proteins have been identified as assembly factors for complex I biogenesis and many patients carrying mutations in genes associated with complex I deficiency and mitochondrial diseases have been discovered. Here, we review the current knowledge of the eukaryotic complex I assembly process and new insights from the identification of novel assembly factors. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes.     

Troponin I phosphorylation in human myocardium in health and disease

Cardiac troponin I (cTnI) is well known as a biomarker for the diagnosis of myocardial damage. However, because of its central role in the regulation of contraction and relaxation in heart muscle, cTnI may also be a potential target for the treatment of heart failure. Studies in rodent models of cardiac disease and human heart samples showed altered phosphorylation at various sites on cTnI (i.e. site-specific phosphorylation). This is caused by altered expression and/or activity of kinases and phosphatases during heart failure development. It is not known whether these (transient) alterations in cTnI phosphorylation are beneficial or detrimental. Knowledge of the effects of site-specific cTnI phosphorylation on cardiomyocyte contractility is therefore of utmost importance for the development of new therapeutic strategies in patients with heart failure. In this review we focus on the role of cTnI phosphorylation in the healthy heart upon activation of the beta-adrenergic receptor pathway (as occurs during increased stress and exercise) and as a modulator of the Frank-Starling mechanism. Moreover, we provide an overview of recent studies which aimed to reveal the functional consequences of changes in cTnI phosphorylation in cardiac disease.     

Tripeptidyl-peptidase II: a multi-purpose peptidase

Tripeptidyl-peptidase II is a high-molecular weight peptidase with a widespread distribution in eukaryotic cells. The enzyme sequentially removes tripeptides from a free N-terminus of longer peptides and also displays a low endopeptidase activity. A role for tripeptidyl-peptidase II in the formation of peptides for antigen presentation has recently become evident, and the enzyme also appears to be important for the degradation of some specific substrates, e.g. the neuropeptide cholecystokinin. However, it is likely that the main biological function of tripeptidyl-peptidase II is to participate in a general intracellular protein turnover. This peptidase may act on oligopeptides generated by the proteasome, or other endopeptidases, and the tripeptides formed would subsequently be good substrates for other exopeptidases. The fact that tripeptidyl-peptidase II activity is increased in sepsis-induced muscle wasting, a situation of enhanced protein turnover, corroborates this biological role.     

Tripeptidyl-peptidase I--distribution, biogenesis, and mechanisms of activation

Tripeptidyl-peptidase I (TPPI) is an acidic lysosomal peptidase that removes tripeptides from an unmodified N-terminus of small proteins and polypeptides. In humans, TPP I constitutes an integral part of the lysosomal proteolytic apparatus, which, includes numerous hydrolytic enzymes, mostly cysteine proteases (cathepsin B, C, H, K, L, and others), but also serine (cathepsin A) and aspartic (cathepsin D) proteases. The combination of endo- and exopeptidase activities of these enzymes allows for efficient digestion of the diverse proteins transported to the lysosomes, releasing free amino acids and dipeptides that are transported back to the cytoplasm and reused according to the metabolic needs of the cell. The role of TPP I in normal lysosome functioning is underscored by the genetic association of the enzyme with one form of a group of the developmental neurodegenerative disorders of childhood--the neuronal ceroid lipofuscinoses (NCLs). The scope of this article is to review the most recent data, mostly from author's laboratory, on the biology and pathology of TPP I. NCLs are also shortly reviewed with the special emphasis on CLN2 form resulting from mutations in TPP I gene.     

Tripeptidyl-peptidase II expression and activity are increased in skeletal muscle during sepsis

We describe a novel protein that contains a verprolin-homology (V) region, through which several actin-regulating proteins, including Wiskott-Aldrich syndrome protein (WASP) family members, bind directly to actin. The amino acid sequence is homologous to the sequences of WASP-interacting protein (WIP) and CR16, both of which associate with WASP and/or N-WASP, and thus these three proteins constitute a new protein family. We named the protein WICH (WIP- and CR16-homologous protein). WICH associates strongly with N-WASP but only weakly with WASP via its C-terminal WASP-interacting (W) region. Ectopic expression of WICH induces actin-microspike formation through cooperation with N-WASP. In addition, expression of the W fragment of WICH suppresses microspike formation induced by N-WASP, indicating an essential role for WICH in N-WASP-induced microspike formation.     

Angiogenesis in health and disease

Blood vessels constitute the first organ in the embryo and form the largest network in our body but, sadly, are also often deadly. When dysregulated, the formation of new blood vessels contributes to numerous malignant, ischemic, inflammatory, infectious and immune disorders. Molecular insights into these processes are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.     

Microchimerism in health and disease

Microchimerism has been defined by the presence of a low number of circulating cells transferred from one individual to another. This transfer takes place naturally during pregnancy, between mother and fetus and/or between fetuses in multi-gestational pregnancies. Furthermore, the establishment of microchimerism can also occur during blood transfusion and organ transplants. Microchimeric cells have been implicated in health and disease. Microchimerism has been correlated with the hyporesponsiveness of the maternal immune system towards the fetal allograft and with the longevity of organ transplants. However, maternal microchimeric cells have been implicated in diseases of the neonate including neonatal graft-versus-host disease, severe combined immunodeficiency and erythema toxicum neonatorum. And more recently, microchimeric cells have been implicated in the pathogenesis of autoimmune diseases including systemic sclerosis and myositis.     

Aquaporins in health and disease

The molecular basis of membrane water-permeability remained elusive until the recent discovery of the aquaporin water-channel proteins. The fundamental importance of these proteins is suggested by their conservation from bacteria through plants to mammals. Ten mammalian aquaporins have thus far been identified, each with a distinct distribution. In the kidney, lung, eye and brain, multiple water-channel homologs are expressed, providing a network for water transport in those locations. It is increasingly clear that alterations in aquaporin expression or function can be rate-limiting for water transport across certain membranes. Aquaporins are likely to prove central to the pathophysiology of a variety of clinical conditions from diabetes insipidus to various forms of edema and, ultimately, they could be a target for therapy in diseases of altered water homeostasis.     

Cytokines in health and disease

Cytokines are cellular regulators of non-immunoglobulin character. The studies of interferon, a representative cytokine, support the view that cytokines are information molecules forming a network in the animal organism. Their main task is to protect the homeostasis of the organism. This may be disturbed both by external and internal causes. The results of the studies of interferon appearing in patients with systems lupus erythematosus do not support the assumption that interferons of this type may play a role in aetiology of autoimmune diseases.     

Magnesium in health and disease

Introduction

Magnesium is an essential electrolyte in living organisms, which has to be supplied daily in a sufficient amount.

Methods

The clinical importance of a magnesium overload or a magnesium intoxication is seldom. However, a magnesium deficiency is of special importance in humans, despite of a normal magnesium supplementation. The primary effect of a magnesium deficiency results in a reduction of energy production. This reduced energy production can result in a disturbed membrane function, calcium magnesium antagonism and cell dysfunction.

Results

Thereby consequences may result in an organ dysfunction and an altered answer to external and internal stress. The reduced energy status is responsible for the recovery of unhealthy individuals - e.g. cardiac arrhythmias, primary hypertension, pre-eclampsia, cramps, allergic reactions—upon repletion of Mg status.

Conclusions

The importance of an oral or intravenously supplementation of magnesium has often been described in a variety of diseases. In addition of special interest is the use of magnesium in critically ill patients in intensive care medicine.     

Leukotrienes in health and disease

The leukotrienes (LTs) are 5-lipoxygenase metabolites of arachidonic acid. The synthesis and release of LTs have been demonstrated in many cells and organs, and LTs are considered to be normal products of continuous metabolism of arachidonic acid. However, although evidence in favor of a critical role for LTs in regulation of physiological functions is still scarce, a growing body of evidence suggests a role for LTs in mediation of several pathophysiological processes such as generalized or local immune reactions, inflammation, asthma, shock, and trauma. LTs have been shown to have potent actions on many essential organs and systems, including the cardiovascular system (heart, blood vessels, microcirculation), the pulmonary system (lung, airways), the central nervous system (neural, glial, and vascular elements), the gastrointestinal tract, and the immune system. In these organs the effects of LTs are mediated by specific LT receptors. Identification of LTs and characterization of their regional and systemic pathological effects, together with characterization of their receptors and elucidation of their structure-activity relationships, are fundamental to developing LT antagonists or synthesis inhibitors that might prevent or reverse LT-dependent reactions. Preliminary reports have already shown that such pharmacological agents ameliorate some aspects of disease processes in experimental animals as well as in humans. In this brief review we intend to highlight the evidence that implicates LTs in normal physiological functions as well as in disease processes.     

Oxytocin in health and disease

Oxytocin is a nonapeptide of the neurohypophyseal protein family that binds specifically to the oxytocin receptor to produce a multitude of central and peripheral physiological responses. Within the central nervous system oxytocin is expressed by the neurons of the hypothalamus that project into higher brain centres and the posterior pituitary gland, from where it enters the circulation by release into the portal capillaries. Centrally, it modulates, maternal, sexual, social and stress related behaviour. Peripheral actions of oxytocin are commonly associated with smooth muscle contraction, particularly within the female and male reproductive tracts. Local synthesis of oxytocin along with its receptor in these regions indicates the presence of local oxytocinergic systems. More sinister implications for oxytocin in autism, depression and several cancers have recently been identified. A greater understanding of the role of oxytocinergic mechanisms will determine the potential for targeting this regulatory peptide in the pharmacological management of these disorders.     

Cholesterol-receptor-mediated genomics in health and disease

Cross-talk between cell-surface receptor C(k) and intracellular receptors (liver X receptor-alpha and peroxisome-proliferator-activated receptors) controls a set of crucial genes that maintain a finely orchestrated balance between various cellular processes involved in cell growth, differentiation, apoptosis, cholesterol homeostasis and inflammation. Abnormal cross-talk of these receptors can lead to several human diseases, particularly atherosclerosis, cancer and autoimmune diseases. As our understanding of the complex signaling events that link these receptors to human health improves, we are beginning to appreciate the enormous potential of the proposed cross-talk model of cholesterol receptors in the prevention and/or treatment of diseases.     

Skeletal remodeling in health and disease

The use of genetically manipulated mouse models, gene and protein discovery and the cataloguing of genetic mutations have each allowed us to obtain new insights into skeletal morphogenesis and remodeling. These techniques have made it possible to identify molecules that are obligatory for specific cellular functions, and to exploit these molecules for therapeutic purposes. New insights into the pathophysiology of diseases have also enabled us to understand molecular defects in a way that was not possible a decade ago. This review summarizes our current understanding of the carefully orchestrated cross-talk between cells of the bone marrow and between bone cells and the brain through which bone is constantly remodeled during adult life. It also highlights molecular aberrations that cause bone cells to become dysfunctional, as well as therapeutic options and opportunities to counteract skeletal loss.