Trends Pharmacol Sci. 2023 May 13;S0165-6147(23)00087-1. doi: 10.1016/j.tips.2023.04.004. 

Striking a gut-liver balance for the antidiabetic effects of metformin

Emma Barroso ¹, Marta Montori-Grau ¹, Walter Wahli ², Xavier Palomer ¹, Manuel Vázquez-Carrera ³

Abstract

Metformin is the most prescribed drug for the treatment of type 2 diabetes mellitus (T2DM), but its mechanism of action has not yet been completely elucidated. Classically, the liver has been considered the major site of action of metformin. However, over the past few years, advances have unveiled the gut as an additional important target of metformin, which contributes to its glucose-lowering effect through new mechanisms of action. A better understanding of the mechanistic details of metformin action in the gut and the liver and its relevance in patients remains the challenge of present and future research and may impact drug development for the treatment of T2DM. Here, we offer a critical analysis of the current status of metformin-driven multiorgan glucose-lowering effects.

• PMID: 37188578
• DOI: 10.1016/j.tips.2023.04.004

Epigenetics Chromatin. 2023 May 19;16(1):19. doi: 10.1186/s13072-023-00493-8.

Premature ovarian insufficiency is associated with global alterations in the regulatory landscape and gene expression in balanced X-autosome translocations

Adriana Di-Battista ^# 1 2, Bianca Pereira Favilla ^# 1, Malú Zamariolli ¹, Natália Nunes ¹, Alexandre Defelicibus ³, Lucia Armelin-Correa ⁴, Israel Tojal da Silva ³, Alexandre Reymond ^# 2, Mariana Moyses-Oliveira ^# 1 5, Maria Isabel Melaragno ^# 6

Abstract

Background: Patients with balanced X-autosome translocations and premature ovarian insufficiency (POI) constitute an interesting paradigm to study the effect of chromosome repositioning. Their breakpoints are clustered within cytobands Xq13-Xq21, 80% of them in Xq21, and usually, no gene disruption can be associated with POI phenotype. As deletions within Xq21 do not cause POI, and since different breakpoints and translocations with different autosomes lead to this same gonadal phenotype, a “position effect” is hypothesized as a possible mechanism underlying POI pathogenesis.

Objective and methods: To study the effect of the balanced X-autosome translocations that result in POI, we fine-mapped the breakpoints in six patients with POI and balanced X-autosome translocations and addressed gene expression and chromatin accessibility changes in four of them.

Results: We observed differential expression in 85 coding genes, associated with protein regulation, multicellular regulation, integrin signaling, and immune response pathways, and 120 differential peaks for the three interrogated histone marks, most of which were mapped in high-activity chromatin state regions. The integrative analysis between transcriptome and chromatin data pointed to 12 peaks mapped less than 2 Mb from 11 differentially expressed genes in genomic regions not related to the patients’ chromosomal rearrangement, suggesting that translocations have broad effects on the chromatin structure.

Conclusion: Since a wide impact on gene regulation was observed in patients, our results observed in this study support the hypothesis of position effect as a pathogenic mechanism for premature ovarian insufficiency associated with X-autosome translocations. This work emphasizes the relevance of chromatin changes in structural variation, since it advances our knowledge of the impact of perturbations in the regulatory landscape within interphase nuclei, resulting in the position effect pathogenicity.

Keywords: Chromatin structure; Position effect; RNA sequencing; X-autosome translocation.

• PMID: 37202802
• PMCID: PMC10197467
• DOI: 10.1186/s13072-023-00493-8

BMC Biol. 2023 May 8;21(1):103. doi: 10.1186/s12915-023-01606-1.

Secondary structure of the human mitochondrial genome affects formation of deletions

Victor Shamanskiy ^# 1, Alina A Mikhailova ^# 1, Evgenii O Tretiakov ^# 2, Kristina Ushakova ^# 1, Alina G Mikhailova ^# 1 3, Sergei Oreshkov ¹, Dmitry A Knorre ⁴, Natalia Ree ¹, Jonathan B Overdevest ⁵, Samuel W Lukowski ⁶, Irina Gostimskaya ^7 8, Valerian Yurov ¹, Chia-Wei Liou ⁹, Tsu-Kung Lin ⁹, Wolfram S Kunz ^10 11, Alexandre Reymond ^12 13, Ilya Mazunin ¹⁴, Georgii A Bazykin ^14 15, Jacques Fellay ¹⁶, Masashi Tanaka ^17 18 19, Konstantin Khrapko ²⁰, Konstantin Gunbin ^1 21, Konstantin Popadin ^22 23 24

Abstract

Background: Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions.

Results: By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a “hot spot” where one deletion breakpoint occurred within the region of 6-9 kb and another within 13-16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6-9 kb and 13-16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470-8482 bp (base pair) and a second arm at 13,447-13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging.

Conclusions: Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.

Keywords: Aging; Contact zone; Deletions; Direct repeats; Global secondary structure; Inverted repeats; Mitochondrial DNA; Single-stranded DNA; mtDNA replication.

• PMID: 37158879
• PMCID: PMC10166460
• DOI: 10.1186/s12915-023-01606-1

Science. 2023 May 5;380(6644):531-536. doi: 10.1126/science.adf9890. Epub 2023 May 4.

Molecular basis of translation termination at noncanonical stop codons in human mitochondria

Martin Saurer ¹, Marc Leibundgut ¹, Hima Priyanka Nadimpalli ², Alain Scaiola ¹, Tanja Schönhut ¹, Richard G Lee ^3 4 5, Stefan J Siira ^3 4, Oliver Rackham ^3 4 5 6, René Dreos ², Tea Lenarčič ¹, Eva Kummer ⁷, David Gatfield ², Aleksandra Filipovska ^3 4 5, Nenad Ban ¹Affiliations expand

Abstract

The genetic code that specifies the identity of amino acids incorporated into proteins during protein synthesis is almost universally conserved. Mitochondrial genomes feature deviations from the standard genetic code, including the reassignment of two arginine codons to stop codons. The protein required for translation termination at these noncanonical stop codons to release the newly synthesized polypeptides is not currently known. In this study, we used gene editing and ribosomal profiling in combination with cryo-electron microscopy to establish that mitochondrial release factor 1 (mtRF1) detects noncanonical stop codons in human mitochondria by a previously unknown mechanism of codon recognition. We discovered that binding of mtRF1 to the decoding center of the ribosome stabilizes a highly unusual conformation in the messenger RNA in which the ribosomal RNA participates in specific recognition of the noncanonical stop codons.

• PMID: 37141370
• DOI: 10.1126/science.adf9890

Nat Commun. 2023 May 3;14(1):2533. doi: 10.1038/s41467-023-38148-7.

Identification of biomarkers for glycaemic deterioration in type 2 diabetes

Roderick C Slieker ^# 1 2, Louise A Donnelly ^# 3, Elina Akalestou ^# 4, Livia Lopez-Noriega ⁴, Rana Melhem ⁵, Ayşim Güneş ⁶, Frederic Abou Azar ⁵, Alexander Efanov ⁷, Eleni Georgiadou ⁴, Hermine Muniangi-Muhitu ⁴, Mahsa Sheikh ⁴, Giuseppe N Giordano ⁸, Mikael Åkerlund ⁸, Emma Ahlqvist ⁸, Ashfaq Ali ⁹, Karina Banasik ¹⁰, Søren Brunak ¹⁰, Marko Barovic ¹¹, Gerard A Bouland ², Frédéric Burdet ¹², Mickaël Canouil ¹³, Iulian Dragan ¹², Petra J M Elders ¹⁴, Celine Fernandez ⁸, Andreas Festa ^15 16, Hugo Fitipaldi ⁸, Phillippe Froguel ^13 17, Valborg Gudmundsdottir ^18 19, Vilmundur Gudnason ^18 19, Mathias J Gerl ²⁰, Amber A van der Heijden ¹⁴, Lori L Jennings ²¹, Michael K Hansen ²², Min Kim ^9 23, Isabelle Leclerc ^4 5, Christian Klose ²⁰, Dmitry Kuznetsov ¹², Dina Mansour Aly ⁸, Florence Mehl ¹², Diana Marek ¹², Olle Melander ⁸, Anne Niknejad ¹², Filip Ottosson ^8 24, Imre Pavo ¹⁵, Kevin Duffin ⁷, Samreen K Syed ⁷, Janice L Shaw ⁷, Over Cabrera ⁷, Timothy J Pullen ^4 25, Kai Simons ²⁰, Michele Solimena ^11 26, Tommi Suvitaival ⁹, Asger Wretlind ⁹, Peter Rossing ^9 27, Valeriya Lyssenko ^28 29, Cristina Legido Quigley ^9 23, Leif Groop ^8 30, Bernard Thorens ³¹, Paul W Franks ^8 32, Gareth E Lim ⁵, Jennifer Estall ⁶, Mark Ibberson ¹², Joline W J Beulens ^1 33, Leen M ‘t Hart ^34 35 36, Ewan R Pearson ³⁷, Guy A Rutter ^38 39 40Affiliations expand

Abstract

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

• PMID: 37137910
• DOI: 10.1038/s41467-023-38148-7

Nat Neurosci. 2023 Apr 20. doi: 10.1038/s41593-023-01313-8. Online ahead of print.

Do all norepinephrine surges disrupt sleep?

Anita Lüthi ¹, Paul Franken ², Stephany Fulda ³, Francesca Siclari ^4 5 6, Eus J W Van Someren ^4 7 8

ARISING FROM: C. Kjaerby et al. Nature Neuroscience https://doi.org/10.1038/s41593-023-01314-7 (2023). Excessive fragmentation of sleep by arousals negatively impacts health. In a recent study in mice, Kjaerby et al. interpret surges of norepinephrine as sleep-fragmenting arousals. As a group of researchers working on human and rodent sleep, we caution against the interpretation that all sleep-related norepinephrine surges invariably indicate arousal. More work is needed to distinguish norepinephrinergic activity characterizing sound versus fragmented sleep.

• PMID: 37081297
• DOI: 10.1038/s41593-023-01313-8