Biology subjects

Mesaros, A.

Publications and source records attributed to Mesaros, A..

6 recordsLinked to original sources

bioRxiv2025

Metabolic immunity to infection is driven by mitochondrial one-carbon metabolism

As large consumers of cellular metabolites, mitochondria are positioned to compete with invading microbes for the nutrients they require to grow. Yet, little is known of whether cells weaponize mitochondrial metabolism during infection. We found that the transcription factor ATF4 activated a mitochondrial metabolic defense based on the essential B vitamin folate. During infection with the human parasite Toxoplasma gondii, ATF4 increased mitochondrial DNA (mtDNA) levels by driving the one-carbon (1C) metabolism processes that occur in mitochondria and use folate. The activation of ATF4 depended on host detection of parasite effector proteins, and restricted parasite growth by limiting its access to folate(s) required for dTMP synthesis. Impairing host mitochondrial 1C metabolism downstream of ATF4 promoted parasite growth, while forcing host dependence on mitochondrial 1C metabolism had the opposite effect. ATF4 activation also promoted a host-protective response in a mouse model of Toxoplasma infection. Thus, ATF4 rewires mitochondrial metabolism to activate a folate-based metabolic immunity against Toxoplasma. Our work paves the way for future studies exploring noncanonical defense strategies mediated by mitochondria and the role of folate metabolism during infectious disease. One-Sentence SummaryATF4 rewires mitochondrial metabolism during infection to drive a host-protective response based on folate competition.

cell biology↗

bioRxiv2024

Increased mitochondrial transcription initiation does not promote oxidative phosphorylation

POLRMT is the sole RNA polymerase in human mitochondria where it generates primers for mitochondrial DNA (mtDNA) replication and transcribes the mitochondrial genome to express genes encoding essential components of the oxidative phosphorylation (OXPHOS) system. Elevated POLRMT levels are found in several cancers and in mouse models with severe mitochondrial dysfunction. Here, we generated and characterized mice over-expressing Polrmt to investigate the physiological and molecular consequences of elevated POLRMT levels. Increasing POLRMT did not result in any pathological phenotype but instead positively affected exercise capacity under stress conditions. POLRMT overexpression increased in organello transcription initiation, resulting in higher steady-state levels of the promoter-proximal L-strand transcript 7S RNA and higher mtDNA levels. Surprisingly, the abundance of mature mitochondrial RNAs was not affected by the elevated POLRMT levels. Furthermore, ubiquitous simultaneous overexpression of POLRMT and LRPPRC, which stabilizes mitochondrial messenger RNAs, did not increase steady-state levels of mitochondrial transcripts in the mouse. Our data show that POLRMT levels regulate transcription initiation, but additional regulatory steps downstream of transcription initiation and transcript stability limit OXPHOS biogenesis.

molecular biology↗

bioRxiv2023

Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes

The mammalian respiratory chain complexes I, III2 and IV (CI, CIII2 and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI- CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knock-in mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in the mouse, but raises questions about their alternate functions, such as relating to regulation of protein stability and prevention of age-associated protein aggregation.

molecular biology↗

bioRxiv2022

Reduced insulin signalling in neurons induces sex-specific health benefits

Reduced activity of the insulin/IGF signalling (IIS) network extends healthspan and lifespan in mammals and possibly humans. Loss of the Irs1 gene increases survival in mice and causes tissue-specific changes in gene expression. However, the tissues underlying IIS mediated longevity are currently unknown. Here we measured survival and healthspan in male and female animals lacking Irs1 activity specifically in the liver, muscle, fat and brain. Tissue-specific loss of IRS1 did not increase survival, suggesting that lack of Irs1 in more than one tissue is required for lifespan extension. Furthermore, loss of Irs1 in liver, muscle and fat did not improve health at old age. In contrast, loss of neuronal Irs1 increased energy expenditure, locomotion and insulin sensitivity, specifically in old males. Neuronal loss of IRS1 also caused male-specific mitochondrial dysfunction, activation of Atf4 and metabolic adaptations consistent with an activated integrated stress response at old age. Thus, we identified a male-specific brain signature of ageing in response to reduced IIS associated with improved health outcomes at old age.

neuroscience↗

bioRxiv2022

Hexosamine pathway activation improves memory but does not extend lifespan in mice.

Glucosamine feeding and genetic activation of the hexosamine biosynthetic pathway (HBP) have been linked to improved protein quality control and lifespan extension in various species. Thus, there is considerable interest in the potential health benefits of dietary supplementation with glucosamine or other HBP metabolites in people. The HBP is a sensor for energy availability and its activation has been implicated in tumor progression and diabetes in higher organisms. As the activation of the HBP has been linked to longevity in lower animals, it is imperative to explore the long-term effects of chronic HBP activation in mammals, which has not been examined so far. To address this issue, we activated the HBP in mice both genetically and through metabolite supplementation, and evaluated metabolism, memory, and survival. GlcNAc supplementation in the drinking water had no adverse effect on weight gain in males but increased weight in young female mice. Glucose or insulin tolerance were not affected up to 20 months of age. Of note, we observed improved memory in the Morris water maze in young male mice supplemented with GlcNAc. Survival was not changed by GlcNAc supplementation. To assess the effects of genetic HBP activation we overexpressed the key enzyme GFAT1 as well as a constitutively activated point mutant form in all mouse tissues. We detected elevated UDP-GlcNAc levels in mouse brains, but did not find any effects on behavior, memory, or survival. Together, while dietary GlcNAc supplementation did not extend survival in mice, it positively affected memory and is generally well tolerated.

physiology↗

bioRxiv2020

Deregulated mito-nuclear communication alters chromatin plasticity and differentiation potential of mesenchymal stem cells upon ageing

Ageing is accompanied by a general decline in the function of many cellular pathways, with metabolic alterations, epigenetic modifications, and stem cell exhaustion representing three important hallmarks of the ageing process. However, whether these pathways are causally or functionally related at a molecular level remains poorly understood. Here, we use bone marrow-derived mesenchymal stem cells (MSCs) isolated from young and old mice to address how age-dependent changes in metabolism and epigenetics are linked and how they impact on the ageing transcriptome and differentiation potential. Given that MSCs maintain specific age-associated properties even under prolonged culture conditions, such as the age-dependent decrease in osteogenic differentiation, they are an excellent model to investigate in vitro the connection of ageing hallmarks on a mechanistic level. In this study, we demonstrate that upon ageing, osteogenic potential of MSCs declines as a consequence of deregulated mito-nuclear communication, mediated by decreased levels of the citrate carrier (CiC). Age-dependent down-regulation of CiC results in acetyl-CoA trapping within mitochondria, hypo-acetylation of histones and chromatin compaction. Together, these changes lead to an altered transcriptional output and are responsible for the reduced differentiation capacity into osteoblasts. Strikingly, short-term supplementation of aged cells with acetate, an exogenous source for cytosolic acetyl-CoA production, rescues not only the age-associated reduction of histone acetylation, but also the osteogenesis defect, representing a potential target for in vitro MSC rejuvenation.

cell biology↗