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1.
Trends Pharmacol Sci ; 45(3): 225-242, 2024 03.
Article in English | MEDLINE | ID: mdl-38402076

ABSTRACT

High levels of pathogenic mitochondrial DNA (mtDNA) variants lead to severe genetic diseases, and the accumulation of such mutants may also contribute to common disorders. Thus, selecting against these mutants is a major goal in mitochondrial medicine. Although mutant mtDNA can drift randomly, mounting evidence indicates that active forces play a role in the selection for and against mtDNA variants. The underlying mechanisms are beginning to be clarified, and recent studies suggest that metabolic cues, including fuel availability, contribute to shaping mtDNA heteroplasmy. In the context of pathological mtDNAs, remodeling of nutrient metabolism supports mitochondria with deleterious mtDNAs and enables them to outcompete functional variants owing to a replicative advantage. The elevated nutrient requirement represents a mutant Achilles' heel because small molecules that restrict nutrient consumption or interfere with nutrient sensing can purge cells of deleterious mtDNAs and restore mitochondrial respiration. These advances herald the dawn of a new era of small-molecule therapies to counteract pathological mtDNAs.


Subject(s)
DNA, Mitochondrial , Mitochondria , Humans , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Mitochondria/metabolism
2.
Nat Commun ; 15(1): 611, 2024 Jan 19.
Article in English | MEDLINE | ID: mdl-38242869

ABSTRACT

Genetic screens have been used extensively to probe interactions between nuclear genes and their impact on phenotypes. Probing interactions between mitochondrial genes and their phenotypic outcome, however, has not been possible due to a lack of tools to map the responsible polymorphisms. Here, using a toolkit we previously established in Drosophila, we isolate over 300 recombinant mitochondrial genomes and map a naturally occurring polymorphism at the cytochrome c oxidase III residue 109 (CoIII109) that fully rescues the lethality and other defects associated with a point mutation in cytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemical assays and phenotypic analyses, we show that the CoIII109 polymorphism modulates cardiolipin binding to prevent complex IV instability caused by the CoIT300I mutation. This study demonstrates the feasibility of genetic interaction screens in animal mitochondrial DNA. It unwraps the complex intra-genomic interplays underlying disorders linked to mitochondrial DNA and how they influence disease expression.


Subject(s)
Cardiolipins , DNA, Mitochondrial , Animals , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Cardiolipins/genetics , Cardiolipins/metabolism , Electron Transport Complex IV/metabolism , Synthetic Lethal Mutations , Mitochondria/genetics , Mitochondria/metabolism , Drosophila/genetics
3.
Biomed Opt Express ; 14(12): 6410-6421, 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-38420303

ABSTRACT

Pathogenic microbes contribute to several major global diseases that kill millions of people every year. Bloodstream infections caused by these microbes are associated with high morbidity and mortality rates, which are among the most common causes of hospitalizations. The search for the "Holy Grail" in clinical diagnostic microbiology, a reliable, accurate, low cost, real-time, and easy-to-use diagnostic method, is one of the essential issues in clinical practice. These very critical conditions can be met by Raman tweezers in combination with advanced analysis methods. Here, we present a proof-of-concept study based on Raman tweezers combined with spectral mixture analysis that allows for the identification of microbial strains directly from human blood serum without user intervention, thus eliminating the influence of a data analyst.

4.
Zookeys ; 693: 109-128, 2017.
Article in English | MEDLINE | ID: mdl-38464884

ABSTRACT

All important published records for 11 moth fly species known so far from Ukraine are reviewed (Phlebotominae 10 species, Psychodinae 1 species). Occurrences of two problematic taxa, Phlebotomus (Adlerius) brevis Theodor & Mesghali, 1964 and P. (Larroussius) major major Annandale, 1910, and some synonymies are discussed. Threticusnegrobovi Vaillant, 1972 must be deleted for Ukraine (misstatement). First records of 34 species of Psychodinae (tribes Mormiini, Paramormiini, Psychodini, Pericomaini) and one of Sycoracinae from Ukraine are also listed.

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