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PXD033362

PXD033362 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleBioenergetic phenotyping of DEN-induced hepatocellular carcinoma reveals a link between adenylate kinase isoform expression and reduced complex I-supported respiration.
DescriptionHepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. Increasing evidence suggests that mitochondria play a central role in malignant metabolic reprogramming in HCC, which may promote disease progression. To comprehensively evaluate the mitochondrial phenotype present in HCC, we applied a recently developed diagnostic workflow that combines high-resolution respirometry, fluorometry, and mitochondrial-targeted nLC-MS/MS proteomics to cell culture (AML12 and Hepa 1-6 cells) and diethylnitrosamine (DEN)-induced mouse models of HCC. Across both model systems, CI-linked respiration was significantly decreased in HCC compared to nontumor, though this did not alter ATP production rates. Interestingly, CI-linked respiration was found to be restored in DEN-induced tumor mitochondria through acute in vitro treatment with P1, P5-di(adenosine-5′) pentaphosphate (Ap5A), a broad inhibitor of adenylate kinases. Mass spectrometry-based proteomics revealed that DEN-induced tumor mitochondria had increased expression of adenylate kinase isoform 4 (AK4), which may account for this response to Ap5A. Tumor mitochondria also displayed a reduced ability to retain calcium and generate membrane potential across a physiological span of ATP demand states compared to DEN-treated nontumor or saline-treated liver mitochondria. We validated these findings in flash-frozen human primary HCC samples, which similarly displayed a decrease in mitochondrial respiratory capacity that disproportionately affected CI. Our findings support the utility of mitochondrial phenotyping in identifying novel regulatory mechanisms governing cancer bioenergetics.
HostingRepositoryjPOST
AnnounceDate2023-04-22
AnnouncementXMLSubmission_2023-04-21_08:00:09.669.xml
DigitalObjectIdentifier
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterKelsey Fisher-Wellman
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListS-carboxamidomethyl-L-cysteine; L-methionine sulfoxide; TMT6plex reporter+balance reagent N-acylated residue; TMT6plex reporter+balance reagent acylated N-terminal
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-04-21 08:46:57ID requested
12023-04-21 08:00:10announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: mitochondria, hepatocellular carcinoma, tumor, diethylnitrosamine
Contact List
Kelsey Fisher-Wellman
lab head
Kelsey Fisher-Wellman
contact affiliationEast Carolina Diabetes and Obesity Institute
dataset submitter
Full Dataset Link List
jPOST dataset URI
Dataset FTP location
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