Neuroscience Bulletin, Год журнала: 2025, Номер unknown
Опубликована: Янв. 7, 2025
Язык: Английский
Analytica Chimica Acta, Год журнала: 2025, Номер 1348, С. 343820 - 343820
Опубликована: Фев. 19, 2025
Язык: Английский
Процитировано
1
Nature Communications, Год журнала: 2025, Номер 16(1)
Опубликована: Март 16, 2025
Abstract Lactate dehydrogenase B (LDHB) fuels oxidative cancer cell metabolism by converting lactate to pyruvate. This study uncovers LDHB’s role in countering mitochondria-associated ferroptosis independently of lactate’s function as a carbon source. LDHB silencing alters mitochondrial morphology, causes lipid peroxidation, and reduces viability, which is potentiated the inducer RSL3. Unlike LDHA, acts parallel with glutathione peroxidase 4 (GPX4) dihydroorotate (DHODH) suppress decreasing ubiquinone (coenzyme Q, CoQ) ubiquinol (CoQH2) ratio. Indeed, supplementation mitoCoQH2 (mitochondria-targeted analogue CoQH2) suppresses peroxidation death after combined RSL3 treatment, consistent presence fraction containing inner membrane. Addressing underlying molecular mechanism, an vitro NADH consumption assay purified human reveals that catalyzes transfer reducing equivalents from CoQ efficiency this reaction increases addition lactate. Finally, radiation therapy induces tumor growth, further enhanced when silencing. Thus, LDHB-mediated oxidation drives CoQ-dependent suppression ferroptosis, promising target for combination therapies.
Язык: Английский
Процитировано
1
Antioxidants, Год журнала: 2023, Номер 12(8), С. 1652 - 1652
Опубликована: Авг. 21, 2023
Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extra-mitochondrial. In addition to its key role oxidative phosphorylation, CoQ10 serves as lipid soluble antioxidant plays an important fatty acid beta-oxidation pyrimidine lysosomal metabolism, well directly mediating the expression genes, including those involved inflammation. Due multiplicity roles cell function, it is not surprising that deficiency been implicated pathogenesis wide range disorders. broadly divided into primary secondary types. Primary results from mutations genes biosynthetic pathway. man, at least 10 are required for biosynthesis functional CoQ10, mutation any one which can result deficit status. Patients may respond oral supplementation, although condition must be recognised sufficiently early, before irreversible tissue damage occurred. this article, we have reviewed clinical studies (up March 2023) relating identification these deficiencies, therapeutic outcomes supplementation; attempted resolve disparities between previous review articles regarding usefulness or otherwise supplementation addition, highlighted several potential problems deficiency, identifying unresolved issues disorders require further research.
Язык: Английский
Процитировано
22
Nature Structural & Molecular Biology, Год журнала: 2024, Номер 31(9), С. 1413 - 1425
Опубликована: Май 20, 2024
Язык: Английский
Процитировано
7
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Март 13, 2025
Nucleotides are essential for nucleic acid synthesis, signaling, and metabolism, can be synthesized de novo or through salvage. Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited target cancer therapy. However, resistance frequently emerges, highlighting the need deeper understanding regulation. Here, we harness uridine salvage CRISPR-Cas9 screening to reveal regulators pyrimidine synthesis. We identify several factors report that synthesis continue in absence coenzyme Q (CoQ), canonical electron acceptor further investigate NUDT5 its conserved interaction with PPAT, rate-limiting enzyme purine show NUDT5, hyperactive siphons phosphoribosyl pyrophosphate (PRPP) pool at expense promoting chemotherapy. Intriguingly, between PPAT appears disrupted by PRPP, intricate allosteric Our findings fundamental mechanism maintaining balance position as potential biomarker predicting
Язык: Английский
Процитировано
1
Nature Catalysis, Год журнала: 2024, Номер 7(2), С. 148 - 160
Опубликована: Янв. 3, 2024
Metabolons are protein assemblies that perform a series of reactions in metabolic pathway. However, the general importance and aptitude metabolons for enzyme catalysis remain poorly understood. In animals, biosynthesis coenzyme Q is currently attributed to ten different proteins, with COQ3, COQ4, COQ5, COQ6, COQ7 COQ9 forming iconic COQ metabolon. Yet several reaction steps conducted by metabolon enigmatic. To elucidate prerequisites animal biosynthesis, we sought construct entire vitro. Here show this approach, rooted ancestral sequence reconstruction, reveals enzymes responsible uncharacterized captures biosynthetic pathway We demonstrate COQ8, kinase, increases streamlines production. Our findings provide crucial insight into how biocatalytic efficiency regulated enhanced these engines context cell.
Язык: Английский
Процитировано
6
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(16), С. 8626 - 8626
Опубликована: Авг. 7, 2024
This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor pathogenesis various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. highlighted critical RGCs, provide metabolic support, regulate cellular health, respond to stress while also producing reactive oxygen species (ROS) that can damage components. Maintaining mitochondrial function meeting RGCs’ high demands ensuring redox homeostasis, crucial their proper health. Oxidative stress, exacerbated by factors like elevated intraocular pressure environmental factors, contributes diseases such as glaucoma vision loss triggering pathways. Strategies targeting or bolstering antioxidant defenses include mitochondrial-based therapies, gene transplantation. These advances offer potential strategies addressing retina, with implications extend beyond ocular diseases.
Язык: Английский
Процитировано
6
Cell Reports, Год журнала: 2024, Номер 43(5), С. 114148 - 114148
Опубликована: Май 1, 2024
pathogenic variant induces cardiac insufficiency and neurodevelopmental delay in mice d Consequently, with Coq2 mutations exhibit perinatal lethality 4HB stimulates mitochondrial metabolism human cells COQ2 defects rescues multisystemic disease prevents the A252V model
Язык: Английский
Процитировано
5
Antioxidants, Год журнала: 2023, Номер 12(7), С. 1391 - 1391
Опубликована: Июль 6, 2023
Coenzyme Q (CoQ) is an essential lipid with many cellular functions, such as electron transport for respiration, antioxidant protection, redox homeostasis, and ferroptosis suppression. Deficiencies in CoQ due to aging, genetic disease, or medication can be ameliorated by high-dose supplementation. As such, understanding of the uptake may inform methods clinical use identify how better treat deficiency. Here, we review what known about intracellular distribution from yeast, mammalian cell culture, rodent models, well its absorption at organism level. We discuss these model organisms probe mechanisms distribution. The literature indicates that are multifaceted processes likely have redundancies transport, utilizing endomembrane system newly identified proteins function transporters. Impairment trafficking either endogenous exogenous exerts profound effects on metabolism stress response. This also highlights significant gaps our knowledge distributed within suggests future directions research understand this process.
Язык: Английский
Процитировано
10
The EMBO Journal, Год журнала: 2024, Номер 43(2), С. 168 - 195
Опубликована: Янв. 11, 2024
Abstract Coenzyme Q (CoQ) is essential for mitochondrial respiration and required thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic BAT stress signals causing accumulation cytosolic RNAs activation the eIF2α kinase PKR, resulting integrated response (ISR) with suppression UCP1 induction FGF21 expression. Strikingly, despite diminished levels, displays increased whole-body metabolic rates at room temperature thermoneutrality decreased weight gain on high-fat diets (HFD). In line enhanced rates, inguinal white tissue (iWAT) interorgan crosstalk caused browning iWAT BAT-specific deficient animals. This mitohormesis-like effect depends ATF4-FGF21 axis BAT-secreted FGF21, revealing an unexpected role modulation energy expenditure wide-ranging implications primary secondary deficiencies.
Язык: Английский
Процитировано
4