Koufos, O. | Search bioRxiv

bioRxiv2023

Fatty acid oxidation drives hydrogen peroxide production by α-ketoglutarate dehydrogenase

Here, we conducted the first in-depth investigation into sex effects on mitochondrial hydrogen peroxide (mH2O2) generation in hepatic tissue. Female liver mitochondria produce less mH2O2 when oxidizing pyruvate, palmitoyl-carnitine, and succinate when compared to male samples. This difference was attributed to superior coupling between fuel metabolism and oxidative phosphorylation (OxPhos) in female liver mitochondria. Examination of mH2O2 production by individual sites of generation revealed that KGDH was a major source in both male and female liver mitochondria oxidizing pyruvate and malate. Surprisingly, -keto-{beta}-methyl-n-valeric acid (KMV), a site-specific inhibitor for KGDH, nearly abolished mH2O2 generation in both male and female liver mitochondria oxidizing palmitoyl-carnitine. KMV did not interfere with the fatty acid oxidation (FAO) pathway and was specific to KGDH. KMV inhibited mH2O2 production in liver mitochondria from male and female mice oxidizing myristoyl, octanoyl, and butyryl-carnitine. We also supply evidence that KGDH, not complex I or complex III, is the major mH2O2 generator in liver mitochondria. Together, we discovered KGDH is a major mH2O2 source, regardless of sex and during FAO.

biochemistry↗

bioRxiv2023

Tumour Extracellular Vesicles Induce Neutrophil Extracellular Traps To Promote Lymph Node Metastasis

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastasis status. However, there is evidence suggesting that LN metastasis is facilitated by a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. We have previously reported that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition abolishes LN metastases in animal mode. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings are the first to reveal the role of EV induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities. Graphic AbstractIllustrative demonstration of the LNs premetastatic niche formation induced by EVs and NETs. Primary tumour constantly secretes EVs, which were actively uptaken by LECs. LECs subsequently secretes CXCL8 or CXCL2 upon EV reception. CXCL8 and CXCL2 are both neutrophil chemoattractants and potent NETs inducers. The following neutrophil recruitment and NETs formation lead to increased LN metastasis burden. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/532413v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@c0c371org.highwire.dtl.DTLVardef@15f6a92org.highwire.dtl.DTLVardef@14dbeedorg.highwire.dtl.DTLVardef@131d3eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗