ABSTRACT
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.
ABSTRACT
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.
Subject(s)
DNA, Mitochondrial/genetics , Embryonic Development/genetics , Maternal Inheritance/genetics , Mitochondria/genetics , Oogenesis/genetics , Animals , Cell Line , Embryo, Mammalian , Female , Fibroblasts , Haplotypes , Male , Mice , Mice, Inbred C57BL , OocytesABSTRACT
UNLABELLED: Metabolic syndrome (MS) is a disease with an inflammatory component. Telmisartan improves insulin resistance in MS, but its relationship with the inflammatory state is unknown. We investigated the effect of 3-month telmisartan therapy on homeostatic model assessment-insulin resistance (HOMA-IR) in hypertensive subjects with MS with regard to the levels of circulating plasma cytokines. METHODS: A total of 42 patients were included in this study; 30 were men (71%), aged 50 ± 8.2 years (mean ± SD). Cytokines and metabolic parameters were analyzed before and after treatment with telmisartan. RESULTS: Twenty-eight patients showed low plasma levels of cytokines (group 1) similar to control subjects, and 14 showed high levels (group 2). Treatment with telmisartan diminished by 35% HOMA-IR in group 1 (4.5 ± 3.1 vs 2.9 ± 2.1), without improvement in group 2. In the multivariate analysis, the predictors of improvement of HOMA-IR in response to telmisartan treatment were low levels of cytokines, whereas systolic and diastolic blood pressure and the elevation of high-sensitivity C-reactive protein had a negative effect. CONCLUSIONS: Our study provides evidence of a more favorable effect of telmisartan on glucose homeostasis in patients with MS and low levels of serum cytokines.
