Mitochondrial Oxidative Phosphorylation Metabolism Research Articles

VLCAD inhibits the proliferation and invasion of hepatocellular cancer cells through regulating PI3K/AKT axis.

Very-long-chain acyl-CoA dehydrogenase (VLCAD) is an essential mediator in fatty acid metabolism. The progression of human hepatocellular carcinoma (HCC) is closely associated with the disorder of energy supply. Here, we aimed to investigate the role and underlying molecule mechanism of VLCAD in pathological process of HCC. In this study, VLCAD was induced silencing and overexpression using small hairpin RNA (shRNA) and lentiviral-mediated vector in HCC cell lines. The proliferation of HCC cells was determined using CCK-8 assay. Transwell assay and lung metastasis were performed to analysis cell metastasis in vitro and in vivo. ECAR and OCR were used to evaluate the activity of glycolysis and mitochondrial oxidative phosphorylation. Our data indicated that VLCAD was downregulated in human HCC tissues and cells. VLCAD overexpression strongly suppressed the proliferation and metastasis of HCC cells associating with the decrease of ATP accumulation and glycolysis activity. Importantly, the PI3K/AKT inhibitor LY294002 strongly abolished the role of shVLCAD in HCC cells. Our results suggested that VLCAD suppressed the growth and metastasis in HCC cells by inhibiting the activities of glycolysis and mitochondrial oxidative phosphorylation metabolism via PI3K/AKT pathway. Together, present findings not only demonstrated the protective role of and molecular network of VLCAD in HCC cells but also indicated its and potential use as a target in the therapy of HCC.

Effects of canagliflozin on growth and metabolic reprograming in hepatocellular carcinoma cells: Multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT).

Metabolic reprograming is crucial in the proliferation of hepatocellular carcinoma (HCC). Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, affects various metabolisms. We investigated the effects of CANA on proliferation and metabolic reprograming of HCC cell lines using multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT). The cells were counted 72 hours after treatment with CANA (10 μM; n = 5) or dimethyl sulfoxide (control [CON]; n = 5) in Hep3B and Huh7 cells. In Hep3B cells, metabolomics and iMPAQT were used to evaluate the levels of metabolites and metabolic enzymes in the CANA and CON groups (each n = 5) 48 hours after treatment. Seventy-two hours after treatment, the number of cells in the CANA group was significantly decreased compared to that in the CON group in Hep3B and Huh7 cells. On multi-omics analysis, there was a significant difference in the levels of 85 metabolites and 68 metabolic enzymes between the CANA and CON groups. For instance, CANA significantly downregulated ATP synthase F1 subunit alpha, a mitochondrial electron transport system protein (CON 297.28±20.63 vs. CANA 251.83±22.83 fmol/10 μg protein; P = 0.0183). CANA also significantly upregulated 3-hydroxybutyrate, a beta-oxidation metabolite (CON 530±14 vs. CANA 854±68 arbitrary units; P<0.001). Moreover, CANA significantly downregulated nucleoside diphosphate kinase 1 (CON 110.30±11.37 vs. CANA 89.14±8.39 fmol/10 μg protein; P = 0.0172). We found that CANA suppressed the proliferation of HCC cells through alterations in mitochondrial oxidative phosphorylation metabolism, fatty acid metabolism, and purine and pyrimidine metabolism. Thus, CANA may suppress the proliferation of HCC by regulating metabolic reprograming.

Obesity, diet and nutraceuticals.

Migraine is the most prevalent neurological disorder worldwide, affecting on average 12% of the general population. Recent data support migraine as part of the metabolic syndrome (MetSyn) spectrum. The evidence of an association between obesity, insulin resistance, and migraine, all having in common the ability to favor a general pro-inflammatory state, reinforces this view. Under a neuronal point of view, another possible link between migraine and MetSyn is, other than the inflammatory state, the cellular energetic deficit. Indeed, it is well known that a mitochondrial energetic dysfunction may play a role in migraine pathogenesis, that MetSyn could further impair mitochondrial metabolism increasing oxidative stress, and that nutraceuticals involved in mitochondrial oxidative phosphorylation (OXPHOS) metabolism (Riboflavin, CoQ10, and magnesium) can be used as migraine prophylactic treatments. Here we review the evidence of MetSyn and migraine association and possible therapeutic implications. There is a close relationship between migraine and MetSyn, especially insulin resistance and obesity. More in detail, obesity is regarded as an important factor of chronification for migraineur patients, while weight-loss seems to have a protective effect. The main player of this association seems to be the obesity-related inflammation and an adequate slimming diet can act to reduce this inflammatory mechanism. In fact, inflammatory cytokines are higher in obese subjects and normalized by weight reduction. Moreover, several foods could act as triggers for some patients by an inflammatory antibody mediated pathway, by a direct histamine or other vasoactive peptides effect, or by modifying the quality and quantity of fat intake. Also, altered insulin metabolism could be related to leptins and nitric oxide (NO) stress, both inducing inflammatory effects involved in migraine pathogenesis. Some prophylactic treatments induce increase of weight, insulin and leptins that can counteract the therapeutic effect; it is the “prophylactic paradox”: a long lasting migraine could be worsened by the drug-induced obesity. Therefore, there is the rationale for the adoption of specific dietetic patterns as complementary treatment in migraine management. In particular, the ketogenic diet is worthy of mention because of its multiple effects on the above-mentioned mechanisms, since it induces a significant weight-loss (when prescribed as very-low calorie diet), normalizes leptins and hyperinsulinemia, improves mitochondrial OXPHOS metabolism, and has a ketone bodies induced anti-inflammatory effect. In summary, more attention should be paid to metabolic implications of migraine and its treatment to further improve, or at least not worsen, patients’ conditions and reduce migraine-related comorbidities and complications.