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Background: Mitochondrial DNA (mtDNA) pathogenic variants have been reported in several solid tumors including ovarian cancer (OC), the most lethal gynecologic malignancy, and raised interest as they potentially induce mitochondrial dysfunction and rewiring of cellular metabolism. Despite advances in recent years, functional characterization of mtDNA variants in cancer and their possible modulation of drug response remain largely uncharted., Methods: Here, we characterized mtDNA variants in OC patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels., Results: Genetic analysis revealed that mtDNA variants predicted as pathogenic, mainly involving complex I and IV genes, were present in all but one PDX (n = 20) at different levels of heteroplasmy, including 7 PDXs with homoplasmic variants. Functional analyses demonstrated that pathogenic mtDNA variants impacted on respiratory complexes activity and subunits abundance as well as on mitochondrial morphology. Moreover, PDX cells bearing homoplasmic mtDNA variants behaved as glucose-addicted and could barely survive glucose starvation in vitro. RNA-seq analysis indicated that mtDNA mutated (heteroplasmy > 50%) PDXs were endowed with upregulated glycolysis and other pathways connected with cancer metabolism. These findings led us to investigate whether pathogenic mtDNA variants correlated with response to anti-VEGF therapy, since the latter was shown to reduce glucose availability in tumors. Strikingly, PDXs bearing homoplasmic pathogenic mtDNA variants associated with improved survival upon anti-VEGF treatment in mice, compared with mtDNA wild type or low heteroplasmy PDXs., Conclusions: These results hint at mtDNA variants as potential biomarkers of response to antiangiogenic drugs., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures involving animals and their care adhere to institutional guidelines that comply with national and international laws and policies (EEC Council Directive 2010/63/EU, OJ L 276, 20.10.2010). The animal study was reviewed and approved by the Italian Ministry of Health (Authorization n. 617/2016-PR), in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declares that they have no competing interests., (© 2024. The Author(s).)

One of the factors limiting the duration of rat liver storage is the excessive accumulation of catabolites in the perfusion medium. In view of obtaining of an efficient depuration the authors have introduced a new circuit allowing for the concomittant perfusion of the liver and of the kidneys. The excretion effort of the kidneys is assessed by the estimation of urea nitrogen in the perfusion medium and in the urine collected over the entire duration of the experiment. The results have confirmed the good function of the system which provides possibilities for improved storage conditions of rat liver.

The dynamics of the fibrinoplastic process were studied in rat isolated liver, perfused in normothermia with a synthetical medium. For the autohistoradiographical study, 125I-labelled fibrinogen was added to the perfusing medium. The historadiograms obtained suggest that the main link in the rise of trans-hepatic vascular resistance is thickening of the fibrin muff of the sinusoids. Consequent reduction of the capillary permeability determines favourable conditions for stasis and massive precipitation of fibrinogen under the form of fibrin thrombi into the intrahepatic vessels. Streptase addition to the perfusion medium prevents the intervention of these mechanisms during the studied period.