BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease

Mitophagy is a highly conserved cellular process that maintains the mitochondrial quantity by eliminating dysfunctional or superfluous mitochondria through autophagy machinery. The mitochondrial outer membrane protein BNIP3L/Nix serves as a mitophagy receptor by recognizing autophagosomes. BNIP3L is initially known to clear the mitochondria during the development of reticulocytes. Recent studies indicated it also engages in a variety of physiological and pathological processes. In this review, we provide an overview of how BNIP3L induces mitophagy and discuss the biological functions of BNIP3L and its regulation at the molecular level. We further discuss current evidence indicating the involvement of BNIP3L-mediated mitophagy in human disease, particularly in cancer and neurological disorders.Subject terms: Cancer, Mitophagy     

Relaxin and the extracellular matrix: molecular mechanisms of action and implications for cardiovascular disease

Myocardial fibrosis is a common endpoint in a variety of cardiac pathologies. It results from excessive accumulation of collagen and other materials that together comprise the extracellular matrix (ECM). In the past decade, the peptide hormone relaxin has emerged as an important regulator of the ECM within several organs, including the heart, and has been suggested as a novel therapeutic agent for the treatment of fibrotic disorders. This review summarises research on the anti-fibrotic actions of relaxin, outlines the potential mechanisms by which relaxin regulates the ECM in cardiovascular tissues and examines the implications of this research for the management of heart disease. Some of the contradictions in the literature are also addressed in order to clarify the role of relaxin as an anti-fibrotic factor in vivo.     

The neurovascular link in health and disease: molecular mechanisms and therapeutic implications

At first sight, the nervous and vascular systems seem to share little in common. However, neural and vascular cells not only are anatomically closely tied to each other, but they also utilize and respond to similar classes of signals to establish correct connectivity and wiring of their networks. Recent studies further provide evidence that this neurovascular crosstalk is more important for understanding the molecular basis of neurological disease than originally anticipated. Moreover, neurovascular strategies offer novel therapeutic opportunities for neurodegenerative disorders.     

The interplay between DNA and histone methylation: molecular mechanisms and disease implications

Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome‐wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA‐ and histone‐modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities.     

Biophysical and molecular mechanisms of ESCRT functions,and their implications for disease

The endosomal sorting complex required for transport (ESCRT) machinery evolved early in evolution to sculpt and cut cellular membranes. Consisting of three subcomplexes termed ESCRT-I, -II and -III, this machinery is recruited to various cellular locations to perform key steps in essential processes such as protein degradation, cell division, and membrane sealing. Here we review recent discoveries that have shed light on biophysical and molecular mechanisms of ESCRTs in endolysosomal protein degradation and nuclear envelope sealing, and we discuss how dysfunctional ESCRTs can lead to diseases such as cancer and neurodegenerative disorders.     

Drug-resistant malaria: molecular mechanisms and implications for public health

Resistance to antimalarial drugs has often threatened malaria elimination efforts and historically has led to the short-term resurgence of malaria incidences and deaths. With concentrated malaria eradication efforts currently underway, monitoring drug resistance in clinical settings complemented by in vitro drug susceptibility assays and analysis of resistance markers, becomes critical to the implementation of an effective antimalarial drug policy. Understanding of the factors, which lead to the development and spread of drug resistance, is necessary to design optimal prevention and treatment strategies. This review attempts to summarize the unique factors presented by malarial parasites that lead to the emergence and spread of drug resistance, and gives an overview of known resistance mechanisms to currently used antimalarial drugs.     

Lithium neuroprotection: molecular mechanisms and clinical implications

Lithium has emerged as a neuroprotective agent efficacious in preventing apoptosis-dependent cellular death. Lithium neuroprotection is provided through multiple, intersecting mechanisms, although how lithium interacts with these mechanisms is still under investigation. Lithium increases cell survival by inducing brain-derived neurotrophic factor and thereby stimulating activity in anti-apoptotic pathways, including the phosphatidylinositol 3-kinase/Akt and the mitogen-activated protein kinase pathways. In addition, lithium reduces pro-apoptotic function by directly and indirectly inhibiting glycogen synthase kinase-3beta activity and indirectly inhibiting N-methyl-D-aspartate (NMDA)-receptor-mediated calcium influx. Lithium-induced regulation of anti- and pro-apoptotic pathways alters a wide variety of downstream effectors, including beta-catenin, heat shock factor 1, activator protein 1, cAMP-response-element-binding protein, and the Bcl-2 protein family. Lithium neuroprotection has a wide variety of clinical implications. Beyond its present use in bipolar mood disorder, lithium's neuroprotective abilities imply that it could be used to treat or prevent brain damage following traumatic injury, such as stroke, and neurodegenerative diseases such as Huntington's and Alzheimer's diseases.     

Molecular mechanisms of RNAi: implications for development and disease

Research over the past few years has led to dramatic new discoveries on the role of double-stranded RNA (dsRNA) in the cell. RNA duplexes have been shown to orchestrate epigenetic changes, repress translation, and direct mRNA degradation in a sequence-specific manner. These diverse effects of dsRNA on gene expression have been termed RNA interference (RNAi). In addition to playing a role in viral defense and silencing transposons, RNAi also has a critical function in a number of developmental processes in the embryo. In this review, we explore these roles and discuss the molecular mechanisms behind dsRNA-mediated gene silencing. Further, we address the use of RNAi as a tool to study gene function in biology, and as a strategy for treating human disease.     

Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics

Alzheimer's disease is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are beta-amyloid (Abeta) plaques, neurofibrillary tangles, synaptic loss and reactive gliosis. The current therapeutic effort is directed towards developing drugs that reduce Abeta burden or toxicity by inhibiting secretase cleavage, Abeta aggregation, Abeta toxicity, Abeta metal interactions or by promoting Abeta clearance. A number of clinical trials are currently in progress based on these different therapeutic strategies and they should indicate which, if any, of these approaches will be efficacious. Current diagnosis of Alzheimer's disease is made by clinical, neuropsychologic and neuroimaging assessments. Routine structural neuroimaging evaluation with computed tomography and magnetic resonance imaging is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of Alzheimer's disease. Functional neuroimaging techniques such as functional magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and single photon emission computed tomography, possibly in conjunction with other related Abeta biomarkers in plasma and CSF, could prove to be valuable in the differential diagnosis of Alzheimer's disease, as well as in assessing prognosis. With the advent of new therapeutic strategies there is increasing interest in the development of magnetic resonance imaging contrast agents and positron emission tomography and single photon emission computed tomography radioligands that will permit the assessment of Abeta burden in vivo.     

Serotonin and energy balance: molecular mechanisms and implications for type 2 diabetes

The neurotransmitter serotonin is an important regulator of energy balance. In the brain, serotonergic fibres from midbrain raphe nuclei project to key feeding centres, where serotonin acts on specific receptors to modulate the activity of various downstream neuropeptide systems and autonomic pathways and thus affects ingestive behaviour and energy expenditure. Serotonin, released by intestinal enterochromaffin cells, also appears to regulate energy homeostasis through peripheral mechanisms. Serotonergic effects on energy balance lead to secondary effects on glucose homeostasis, based on a well-established link between obesity and insulin resistance. However, serotonergic pathways may also directly affect glucose homeostasis through regulation of autonomic efferents and/or action on peripheral tissues. Several serotonergic compounds have been evaluated for clinical use in the treatment of obesity and type 2 diabetes; results of these trials are discussed here. Finally, future directions in the elucidation of serotonergic metabolic regulation are discussed.     

Parkinson disease: from pathology to molecular disease mechanisms

Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death.     

Epigenetics and the environment: emerging patterns and implications

Epigenetic phenomena in animals and plants are mediated by DNA methylation and stable chromatin modifications. There has been considerable interest in whether environmental factors modulate the establishment and maintenance of epigenetic modifications, and could thereby influence gene expression and phenotype. Chemical pollutants, dietary components, temperature changes and other external stresses can indeed have long-lasting effects on development, metabolism and health, sometimes even in subsequent generations. Although the underlying mechanisms remain largely unknown, particularly in humans, mechanistic insights are emerging from experimental model systems. These have implications for structuring future research and understanding disease and development.     

Epigenetics and airways disease

Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. Epigenetic regulation is not only critical for generating diversity of cell types during mammalian development, but it is also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that disruption of epigenetic processes can lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. Furthermore, the expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease.     

Chronic idiopathic thrombocytopenic purpura (ITP): molecular mechanisms and implications for therapy

Chronic idiopathic thrombocytopenic purpura (ITP) is an immune-mediated disorder in which platelets are prematurely destroyed in the reticuloendothelial system by platelet autoantibodies. However, it is becoming clear that the pivotal process of the humoral immune response in the pathogenesis of the disorder is a complex interaction between antigen-presenting cells, T cells and B cells. Furthermore, it is increasingly evident that regulatory T cells play an important role and that T-cell-mediated cytotoxicity contributes to the destruction of platelets in ITP. Different new approaches to immunotherapy in chronic ITP have been explored, including use of anti-CD20, anti-CD154 and anti-CD52 antibodies. So far, these therapies have been antigen-nonspecific and the risk of general immunosuppression is a concern. Thus, improving our understanding of the interaction and relative contribution of humoral and cell-mediated mechanisms is essential for developing antigen-specific immunotherapies for the treatment of this disorder. This review aims to elucidate the current status of knowledge of the cellular and humoral immune components of chronic ITP, together with the implications of this knowledge for therapy.     

Proteolytic mechanisms in amyloid-beta metabolism: therapeutic implications for Alzheimer's disease

The accumulation of the amyloid-beta peptide, the main constituent of the "amyloid plaque", is widely considered to be the key pathological event in Alzheimer's disease. Amyloid-beta is produced from the amyloid precursor protein through the action of the proteases beta-secretase and gamma-secretase. Alternative cleavage of amyloid precursor protein by the enzyme alpha-secretase precludes amyloid-beta production. In addition, several proteases are involved in the degradation of amyloid-beta. This review focuses on the proteolytic mechanisms of amyloid-beta metabolism. An increasingly detailed understanding of proteolysis in both amyloid-beta deposition and clearance has identified some of these proteases as potential therapeutic targets for Alzheimer's disease. A more complex knowledge of these proteases takes us one step closer to developing "disease-modifying" therapies, but these advances also emphasize that significant challenges must be overcome before clinically effective drugs to treat Alzheimer's disease become a reality.