Biology subjects

Saari, S.

Publications and source records attributed to Saari, S..

3 recordsLinked to original sources

bioRxiv2024

Exploring mitonuclear interactions in the regulation of cell physiology: insights from interspecies cybrids

Brown hares (Lepus europaeus) and mountain hares (Lepus timidus) frequently hybridize in regions where their range overlaps, producing fertile offspring and enabling gene flow between the species. Despite this, no hybrid species has emerged, suggesting that hybrid backcrosses may incur fitness costs. One potential mechanism for such costs involves the interactions between mitochondrial and nuclear gene products, where incompatibilities between species-specific alleles may reinforce species barriers and lead to hybrid breakdown. However, direct experimental evidence for this hypothesis remains limited. In this study, we used fibroblasts derived from skin biopsies of wild-caught hares to generate cytoplasmic hybrid (cybrid) cell lines, wherein mitochondria and mtDNA from one species were transferred to mitochondria-depleted cells of the other species, creating novel mitonuclear gene combinations while preserving the original diploid nuclear background. Employing a range of techniques - including transcriptomics, metabolomics, microscopy, and respirometry - we explored the consequences of mitochondrial transfer between these hare species. Our results reveal that in the studied species mitonuclear incompatibilities exhibit strong effects on cellular fitness but are limited to specific genotypes. We propose mechanisms of cellular-level incompatibility and their potential consequences for interspecific hybrids, offering new insights into the complexity of mitonuclear interactions.

cell biology↗

bioRxiv2024

A species difference in glycerol-3-phosphate metabolism reveals metabolic adaptations in hares

The temperate climate adapted brown hare (Lepus europaeus) and the cold-adapted mountain hare (Lepus timidus) are evolutionarily closely related and interfertile. Still, their cultured skin fibroblasts show clear differences in the expression of genes related to basic cellular metabolism. To study this further, we utilized targeted metabolomics analysis, metabolite tracing, and high-resolution respirometry, and identified significant differences in metabolic pathways associated with adaptive thermogenesis, including a higher rate of glycerol 3-phosphate (G3P) production in the mountain hare. We therefore investigated mitochondrial heat production and its dependence on G3P in the two hare species. The mountain hare maintained lower mitochondrial temperature and had weaker thermal change following OXPHOS inhibition. Manipulating mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) levels demonstrated its role in mitochondrial thermogenesis and revealed species-specific function in maintaining mitochondrial membrane potential. This study unveils previously undocumented and unexpected species differences in the mitochondrial properties of fibroblasts that could indicate differences in metabolic adaptability. These findings also demonstrate the utility of cell culture models in assessing trait differences between species and their evolutionary significance, contributing to a deeper understanding of metabolic adaptation in animals and underscoring the potential of in vitro approaches for eco-physiological studies.

molecular biology↗

bioRxiv2021

Systemic impact of the expression of the mitochondrial alternative oxidase on Drosophila development

Despite the beneficial effects of xenotopically expressing the mitochondrial alternative oxidase AOX from Ciona intestinalis in mammalian and insect models, important detrimental outcomes have also been reported, raising concerns regarding its potential deployment as a therapeutic enzyme for human mitochondrial diseases. Because of its non-protonmotive terminal oxidase activity, AOX can bypass the cytochrome segment of the respiratory chain whilst not contributing to mitochondrial ATP synthesis. We have previously shown that pupal lethality occurs when AOX-expressing Drosophila larvae are cultured on a low-nutrient diet, indicating that AOX can perturb normal metabolism during development. Here, combined omics analyses revealed multiple correlates of this diet-dependent lethality, including a general alteration of larval amino acid and lipid metabolism, functional and morphological changes to the larval digestive tract, and a drastic decrease in larval biomass accumulation. Pupae at the pre-lethality stage presented a general downregulation of mitochondrial metabolism and a signature of starvation and deregulated signaling. AOX-induced lethality was partially rescued when the low-nutrient diet was supplemented with tryptophan and/or methionine, but not with proline and/or glutamate, strongly suggesting perturbation of one-carbon metabolism. The developmental dependence on tryptophan and/or methionine, associated with elevated levels of lactate dehydrogenase, 2-hydroxyglutarate, choline-containing metabolites and breakdown products of membrane phospholipids, indicates that AOX expression promotes tissue proliferation and larval growth, but this is ultimately limited by energy dissipation due to partial mitochondrial uncoupling. We speculate that the combination of dietary interventions and AOX expression might, nevertheless, be useful for the metabolic regulation of proliferative tissues, such as tumors.

biochemistry↗