bims-mitran 2023-08-20 papers

Issue of 2023–08–20
four papers selected by
Andreas Kohler, University of Graz

Nature. 2023 Aug 16.

Nuclear genetic control of mtDNA copy number and heteroplasmy in humans.

Rahul Gupta, Masahiro Kanai, Timothy J Durham, Kristin Tsuo, Jason G McCoy, Anna V Kotrys, Wei Zhou, Patrick F Chinnery, Konrad J Karczewski, Sarah E Calvo, Benjamin M Neale, Vamsi K Mootha.

Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation1. Heteroplasmy refers to the presence of a mixture of mtDNA alleles in an individual and has been associated with disease and ageing. Mechanisms underlying common variation in human heteroplasmy, and the influence of the nuclear genome on this variation, remain insufficiently explored. Here we quantify mtDNA copy number (mtCN) and heteroplasmy using blood-derived whole-genome sequences from 274,832 individuals and perform genome-wide association studies to identify associated nuclear loci. Following blood cell composition correction, we find that mtCN declines linearly with age and is associated with variants at 92 nuclear loci. We observe that nearly everyone harbours heteroplasmic mtDNA variants obeying two principles: (1) heteroplasmic single nucleotide variants tend to arise somatically and accumulate sharply after the age of 70 years, whereas (2) heteroplasmic indels are maternally inherited as mixtures with relative levels associated with 42 nuclear loci involved in mtDNA replication, maintenance and novel pathways. These loci may act by conferring a replicative advantage to certain mtDNA alleles. As an illustrative example, we identify a length variant carried by more than 50% of humans at position chrM:302 within a G-quadruplex previously proposed to mediate mtDNA transcription/replication switching2,3. We find that this variant exerts cis-acting genetic control over mtDNA abundance and is itself associated in-trans with nuclear loci encoding machinery for this regulatory switch. Our study suggests that common variation in the nuclear genome can shape variation in mtCN and heteroplasmy dynamics across the human population.

DOI: https://doi.org/10.1038/s41586-023-06426-5

MicroPubl Biol. 2023 ;2023

SHE9 deletion mutants display fitness defects during diauxic shift in Saccharomyces cerevisiae .

Shane J Kowaleski, Christina S Hurmis, Carvin N Coleman, Kieli D Philips, Nicole A Najor.

Saccharomyces cerevisiae protein She9 is localized to the inner mitochondrial membrane and is required for normal mitochondrial morphology. While deletion mutants of SHE9 ( she9Δ ) are viable and display large ring-like mitochondrial structures, the molecular function of SHE9 is still unknown. We report a decreased growth of she9Δ cells during a diauxic shift, where mitochondria are primarily employing oxidative phosphorylation to generate ATP versus the alternative mechanism of glycolysis in high glucose conditions. Further bioinformatics analysis reveal putative functional protein associations, and proposes a model to aid in the understanding of the molecular function of She9.

DOI: https://doi.org/10.17912/micropub.biology.000899

J Autoimmun. 2023 Aug 16. pii: S0896-8411(23)00100-2. [Epub ahead of print]139 103091

Chronic inflammation in high-fat diet-fed mice: Unveiling the early pathogenic connection between liver and adipose tissue.

Heekyong R Bae, Su-Kyung Shin, Ji-Hyeon Yoo, Suntae Kim, Howard A Young, Eun-Young Kwon.

Obesity-induced chronic inflammation has been linked to several autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. The underlying mechanisms are not yet fully understood, but it is believed that chronic inflammation in adipose tissue can lead to the production of pro-inflammatory cytokines and chemokines, which can trigger immune responses and contribute to the development of autoimmune diseases. However, the underlying mechanisms that lead to the infiltration of immune cells into adipose tissue are not fully understood. In this study, we observed a time-dependent response to a high-fat diet in the liver and epididymal white adipose tissue using gene set enrichment analysis. Our findings revealed a correlation between early abnormal innate immune responses in the liver and late inflammatory response in the adipose tissue, that eventually leads to systemic inflammation. Specifically, our data suggest that the dysregulated NADH homeostasis in the mitochondrial matrix, interacting with the mitochondrial translation process, could serve as a sign marking the transition from liver inflammation to adipose tissue inflammation. Taken together, our study provides valuable insights into the molecular mechanisms underlying the development of chronic inflammation and associated autoimmune diseases in obesity.

Keywords: Autoimmune diseases; Chronic inflammation; Mitochondrial translation; NADH homeostasis; Obesity

DOI: https://doi.org/10.1016/j.jaut.2023.103091