MEvoLib v1.0: The first molecular evolution library for Python

Background: Molecular evolution studies involve many different hard computational problems solved, in most cases, with heuristic algorithms that provide a nearly optimal solution. Hence, diverse software tools exist for the different stages involved in a molecular evolution workflow. Results: We present MEvoLib, the first molecular evolution library for Python, providing a framework to work with different tools and methods involved in the common tasks of molecular evolution workflows. In contrast with already existing bioinformatics libraries, MEvoLib is focused on the stages involved in molecular evolution studies, enclosing the set of tools with a common purpose in a single high-level interface with fast access to their frequent parameterizations. The gene clustering from partial or complete sequences has been improved with a new method that integrates accessible external information (e.g. GenBank''s features data). Moreover, MEvoLib adjusts the fetching process from NCBI databases to optimize the download bandwidth usage. In addition, it has been implemented using parallelization techniques to cope with even large-case scenarios. Conclusions: MEvoLib is the first library for Python designed to facilitate molecular evolution researches both for expert and novel users. Its unique interface for each common task comprises several tools with their most used parameterizations. It has also included a method to take advantage of biological knowledge to improve the gene partition of sequence datasets. Additionally, its implementation incorporates parallelization techniques to enhance computational costs when handling very large input datasets

Oxidative phosphorylation system and cell culture media

Traditional culture media do not re-semble the metabolic compositionof human blood. The concentrationof different metabolites in thesemedia influences mitochondrialbiogenesis and oxidative phos-phorylation (OXPHOS) function.This knowledge is essential for theinterpretation of results obtainedfrom cellular models used for thestudy of OXPHOS function

Molecular insights into mitochondrial protein translocation and human disease

In human mitochondria, mtDNA encodes for only 13 proteins, all components of the OXPHOS system. The rest of the mitochondrial components, which make up approximately 99% of its proteome, are encoded in the nuclear genome, synthesized in cytosolic ribosomes and imported into mitochondria. Different import machineries translocate mitochondrial precursors, depending on their nature and the final destination inside the organelle. The proper and coordinated function of these molecular pathways is critical for mitochondrial homeostasis. Here, we will review molecular details about these pathways, which components have been linked to human disease and future perspectives on the field to expand the genetic landscape of mitochondrial diseases. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Effects of tributyltin chloride on cybrids with or without an ATP synthase pathologic mutation

Background: The oxidative phosphorylation system (OXPHOS) includes nuclear chromosome (nDNA)– and mitochondrial DNA (mtDNA)–encoded polypeptides. Many rare OXPHOS disorders, such as striatal necrosis syndromes, are caused by genetic mutations. Despite important advances in sequencing procedures, causative mutations remain undetected in some patients. It is possible that etiologic factors, such as environmental toxins, are the cause of these cases. Indeed, the inhibition of a particular enzyme by a poison could imitate the biochemical effects of pathological mutations in that enzyme. Moreover, environmental factors can modify the penetrance or expressivity of pathological mutations. Objectives: We studied the interaction between mitochondrially encoded ATP synthase 6 (p.MT-ATP6) subunit and an environmental exposure that may contribute phenotypic differences between healthy individuals and patients suffering from striatal necrosis syndromes or other mitochondriopathies. Methods: We analyzed the effects of the ATP synthase inhibitor tributyltin chloride (TBTC), a widely distributed environmental factor that contaminates human food and water, on transmitochondrial cell lines with or without an ATP synthase mutation that causes striatal necrosis syndrome. Doses were selected based on TBTC concentrations previously reported in human whole blood samples. Results: TBTC modified the phenotypic effects caused by a pathological mtDNA mutation. Interestingly, wild-type cells treated with this xenobiotic showed similar bioenergetics when compared with the untreated mutated cells. Conclusions: In addition to the known genetic causes, our findings suggest that environmental exposure to TBTC might contribute to the etiology of striatal necrosis syndromes

Increasing mtDNA levels as therapy for mitochondrial optic neuropathies

Leber hereditary optic neuropathy (LHON) is a rare, inherited mitochondrial disease. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. Primary open-angle glaucoma (POAG) is a frequent, acquired optic neuropathy. Lowering intraocular pressure (IOP) reduces disease progression. However, current methods to decelerate this progression are recognized as being inadequate. Therefore, there is a clear need to look for new therapeutic approaches. The growing evidence indicates that POAG can also be a mitochondrial optic neuropathy (MON). Several risk elements are common for both diseases and all of them decrease mitochondrial (mt)DNA content. Based on these susceptibility factors and their molecular mechanism, we suggest herein pharmacological therapies targeted to increase mtDNA levels, oxidative phosphorylation (OXPHOS) capability, and mitochondrial energy production as treatments for MONs

Oxidative phosphorylation inducers fight pathological angiogenesis

Pathological mutations in subunits of the oxidative phosphorylation (OXPHOS) system, or inhibitors of this biochemical pathway, increase the production of vascular endothelial growth factor (VEGF) and pathological angiogenesis. In many angiogenesis-related diseases, such as retinal, rheumatoid diseases, or cancer, OXPHOS dysfunction can be found. Thus, enhancing OXPHOS might be a promising therapeutic approach for pathologic angiogenesis

Food derived respiratory complex I inhibitors modify the effect of Leber hereditary optic neuropathy mutations

Mitochondrial DNA mutations in genes encoding respiratory complex I polypeptides can cause Leber hereditary optic neuropathy. Toxics affecting oxidative phosphorylation system can also cause mitochondrial optic neuropathy. Some complex I inhibitors found in edible plants might differentially interact with these pathologic mutations and modify their penetrance. To analyze this interaction, we have compared the effect of rotenone, capsaicin and rolliniastatin-1 on cybrids harboring the most frequent Leber hereditary optic neuropathy mutations and found that m.3460G > A mutation increases rotenone resistance but capsaicin and rolliniastatin-1 susceptibility. Thus, to explain the pathogenicity of mitochondrial diseases due to mitochondrial DNA mutations, their potential interactions with environment factors will have to be considered

ZARAMIT: A System for the Evolutionary Study of Human Mitochondrial DNA

Abstract. ZARAMIT is an information system capable of fully auto-mated phylogeny reconstruction. Methods have been tailored to mito-chondrial DNA sequences, with focus on subproblem partitioning. We have built exhaustive human mitochondrial phylogenies (∼5500 sequences) and detected problems in existing haplogroup hierarchies through data-driven classification. Information on the project can be found on zaramit.org. 1 The case for mitochondrial DNA Mitochondria, organelles present in most eukaryotic cells, are responsible for the generation of most of the cell’s chemical energy. They are also remarkable for possessing their own, separate genome, which coexists with nuclear DNA and is inherited independently. Further, mitochondrial DNA (mtDNA) has several features which make it an ideal candidate for conducting evolutionary studies. Firstly, it is small in mammals (15000 to 17000 base pairs) and encodes a homogeneous set of gene

Mitochondrial DNA Haplogroup JT is Related to Impaired Glycaemic Control and Renal Function in Type 2 Diabetic Patients

The association between mitochondrial DNA (mtDNA) haplogroup and risk of type 2 diabetes (T2D) is undetermined and controversial. This study aims to evaluate the impact of the main mtDNA haplogroups on glycaemic control and renal function in a Spanish population of 303 T2D patients and 153 healthy controls. Anthropometrical and metabolic parameters were assessed and mtDNA haplogroup was determined in each individual. Distribution of the different haplogroups was similar in diabetic and healthy populations and, as expected, T2D patients showed poorer glycaemic control and renal function than controls. T2D patients belonging to the JT haplogroup (polymorphism m.4216T>C) displayed statistically significant higher levels of fasting glucose and HbA(1c) than those of the other haplogroups, suggesting a poorer glycaemic control. Furthermore, diabetic patients with the JT haplogroup showed a worse kidney function than those with other haplogroups, evident by higher levels of serum creatinine, lower estimated glomerular filtration rate (eGFR), and slightly higher (although not statistically significant) urinary albumin-to-creatinine ratio. Our results suggest that JT haplogroup (in particular, change at position 4216 of the mtDNA) is associated with poorer glycaemic control in T2D, which can trigger the development of diabetic nephropathy

Pharmacologic concentrations of linezolid modify oxidative phosphorylation function and adipocyte secretome

The oxidative phosphorylation system is important for adipocyte differentiation. Therefore, xenobiotics inhibitors of the oxidative phosphorylation system could affect adipocyte differentiation and adipokine secretion. As adipokines impact the overall health status, these xenobiotics may have wide effects on human health. Some of these xenobiotics are widely used therapeutic drugs, such as ribosomal antibiotics. Because of its similarity to the bacterial one, mitochondrial translation system is an off-target for these compounds. To study the influence of the ribosomal antibiotic linezolid on adipokine production, we analyzed its effects on adipocyte secretome. Linezolid, at therapeutic concentrations, modifies the levels of apolipoprotein E and several adipokines and proteins related with the extracellular matrix. This antibiotic also alters the global methylation status of human adipose tissue-derived stem cells and, therefore, its effects are not limited to the exposure period. Besides their consequences on other tissues, xenobiotics acting on the adipocyte oxidative phosphorylation system alter apolipoprotein E and adipokine production, secondarily contributing to their systemic effects