A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders

\ua9 2024 The AuthorsMitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre

Structure of bryozoan communities in an Antarctic glacial fjord (Admiralty Bay, South Shetlands)

Bryozoans are among the most important groups of the Southern Ocean benthic macrofauna, both in terms of species richness and abundance. However, there is a considerable lack of ecological research focused on their distribution patterns and species richness on smaller scale, especially in the soft bottom habitats of Antarctic glacial fjords. The aim of this study was to describe those patterns in the Admiralty Bay. Forty-nine Van Veen grab samples were collected at the depth range from 15 to 265 m, in the summer season of 1979/1980, at three sites distributed along the main axis of the fjord. Among 53 identified species of bryozoans, 32 were recorded in the Admiralty Bay for the first time. The most common and abundant species were Himantozoum antarcticum, Inversiula nutrix and Nematoflustra flagellata. Genera such as Arachnopusia, Cellarinella and Osthimosia were the most speciose taxa. It was demonstrated that depth was important for the distribution of the bryozoans. More than half of the recorded species were found only below 70 m. An influence of glacial disturbance was reflected in the dominance structure of colony growth-forms. The inner region of the fjord was dominated almost entirely by encrusting species, while the diversity of bryozoan growth-forms in less disturbed areas was much higher. In those sites the highest percentage of branched, tuft like species represented by buguliform and flustriform zoaria was observed.The study was supported by a grant of Polish Ministry of Science and Higher Education No. 51/N-IPY/2007/0 as well as Census of Antarctic Marine Life Project. Krzysztof Pabis was also partially supported by University of Lodz internal funds. This research was also supported by the Polish Geological Institute-National Research Institute during the realization of the project numbered 40.2900.0903.18.0 titled “Bryozoan assemblage of Admiralty Bay—richness, diversity and abundance.” Urszula Hara is deeply grateful to Leszek Giro (Micro-area Analyses Laboratory at the Polish Geological Institute-National Research Institute, Warsaw), for providing SEM assistance during the project. We also want to thank two anonymous reviewers for their suggestions that helped us improve this article. Thanks are also due to Magdalena Błażewicz-Paszkowycz for language correction and polishing the final version of the manuscript

The poly-omics of ageing through individual-based metabolic modelling

Abstract Background Ageing can be classified in two different ways, chronological ageing and biological ageing. While chronological age is a measure of the time that has passed since birth, biological (also known as transcriptomic) ageing is defined by how time and the environment affect an individual in comparison to other individuals of the same chronological age. Recent research studies have shown that transcriptomic age is associated with certain genes, and that each of those genes has an effect size. Using these effect sizes we can calculate the transcriptomic age of an individual from their age-associated gene expression levels. The limitation of this approach is that it does not consider how these changes in gene expression affect the metabolism of individuals and hence their observable cellular phenotype. Results We propose a method based on poly-omic constraint-based models and machine learning in order to further the understanding of transcriptomic ageing. We use normalised CD4 T-cell gene expression data from peripheral blood mononuclear cells in 499 healthy individuals to create individual metabolic models. These models are then combined with a transcriptomic age predictor and chronological age to provide new insights into the differences between transcriptomic and chronological ageing. As a result, we propose a novel metabolic age predictor. Conclusions We show that our poly-omic predictors provide a more detailed analysis of transcriptomic ageing compared to gene-based approaches, and represent a basis for furthering our knowledge of the ageing mechanisms in human cells