Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues

Regulation of mother-to-offspring transmission of mtDNA heteroplasmy

mtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and induced pluripotent stem cell (iPSC) generation. Thus, genetic and pharmacological interventions affecting oxidative phosphorylation (OXPHOS) modify competition among mtDNA haplotypes during oocyte development and/or at early embryonic stages. We show that heteroplasmy behavior can fall on a spectrum from random drift to strong selection, depending on mito-nuclear interactions and metabolic factors. Understanding heteroplasmy dynamics and its mechanisms provide novel knowledge of a fundamental biological process and enhance our ability to mitigate risks in clinical applications affecting mtDNA transmission

Alcaloides de las papilionáceas. XXIX. Estructura y síntesis de la santiaguina

5 páginas.Condensation of isotripiperideine and α-truxilic acid chloride yields a product, C48H66O2N6, m. p. 257-58º, which by subsequent acid hydrolisis produces C38H48O2N4. The latter base and two of its salts as well, do not produce depresion in the melting point of the mixture with the corresponding compounds of “santiaguine”. The I. R. spectra in both substances are identical. From the foregoing it is clear that the “santiaguine” has definitively the structure of N’N’l-α—truxiloil—bis(2’3’-dehydro-α,β’-dipiperidil).Peer reviewe

Los microorganismos orales y su relación con las enfermedades sistémicas: ¿Qué tan informados estamos?

Antecedentes. En la cavidad oral podemos encontrar un ecosistema muy complejo donde los tejidos de la boca interaccionan con una amplia variedad de especies microbianas. Muchas de estas especies forman biopelículas en las superficies de los dientes y generan infecciones bucales como caries, gingivitis y periodontitis. Sin el tratamiento correcto, cada una de estas enfermedades tiene el potencial de convertirse en un foco infeccioso y contribuir al desarrollo de afecciones sistémicas como enfermedades cardiovasculares y gastrointestinales, así como inducir partos prematuros y nacimientos con bajo peso. Objetivo. Debido a las diversas enfermedades sistémicas que pueden surgir a raíz de una mala higiene bucal, en este trabajo el objetivo fue realizar una encuesta a ciudadanos, que nos permita saber sus hábitos de higiene bucal, y conocer qué tanto saben de su relación con las enfermedades sistémicas, así como investigar que estructuras de proteínas depositadas en el PDB (Protein Data Bank) se encuentran en microorganismos orales. Resultados y conclusiones. Los datos obtenidos nos permitieron concluir qué el género femenino tiene ligeramente mayor conocimiento acerca de la relación entre la falta de salud bucal y las enfermedades sistémicas, sin embargo; la mayoría de los participantes desconoce esta relación y considera tener una buena salud bucal a pesar de no acudir regularmente al dentista. En cuanto a las estructuras de proteínas depositadas en el PDB, se encontraron muchas, lo que abre la posibilidad para futuros estudios que nos permitan comprender los procesos de infección que se vinculen con enfermedades sistémicas

Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease with Pulmonary Hypertension and Frailty; 35236094

Background: In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell. Methods: We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism. Results: We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. Conclusions: Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA. © 2022 Lippincott Williams and Wilkins. All rights reserved