bims-mignad 2025-02-23 papers

Issue of 2025–02–23
two papers selected by
Melisa Emel Ermert, Amsterdam UMC

bioRxiv. 2025 Feb 08. pii: 2025.02.07.637120. [Epub ahead of print]

Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.

Kimberly S Huggler, Carlos A Mellado Fritz, Kyle M Flickinger, Gavin R Chang, Meghan F McGuire, Jason R Cantor.

Hexokinase (HK) catalyzes the synthesis of glucose-6-phosphate, marking the first committed step of glucose metabolism. Most cancer cells express two homologous isoforms (HK1 and HK2) that can each bind to the outer mitochondrial membrane (OMM). CRISPR screens across hundreds of cancer cell lines indicate that both are dispensable for cell growth in traditional culture media. By contrast, HK2 deletion impairs cell growth in Human Plasma-Like Medium (HPLM). Here, we find that HK2 is required to maintain sufficient cytosolic (OMM-detached) HK activity under conditions that enhance HK1 binding to the OMM. Notably, OMM-detached rather than OMM-docked HK promotes "aerobic glycolysis" (Warburg effect), an enigmatic phenotype displayed by most proliferating cells. We show that several proposed theories for this phenotype cannot explain the HK2 dependence and instead find that HK2 deletion severely impairs glycolytic ATP production with little impact on total ATP yield for cells in HPLM. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis underlies the Warburg effect.

DOI: https://doi.org/10.1101/2025.02.07.637120

bioRxiv. 2025 Feb 08. pii: 2025.02.05.636725. [Epub ahead of print]

DHRS7 Integrates NADP + /NADPH Redox Sensing with Inflammatory Lipid Signalling via the Oxoeicosanoid Pathway.

Yanan Ma, King Lam Hui, Yohannes A Ambaw, Tobias C Walther, Robert V Farese, Miklos Lengyel, Zaza Gelashvili, Dajun Lu, Philipp Niethammer.

During the innate immune response at epithelial wound sites, oxidative stress acts microbicidal and-mechanistically less well understood-as an immune and resilience signal. The reversible sulfhydryl (SH) oxidation of kinases, phosphatases, and transcription factors constitute the perhaps best-known redox signalling paradigm, whereas mechanisms that transduce metabolic redox cues, such as redox cofactor balance, remain little explored. Here, using mammalian cells, microsomes, and live zebrafish, we identify DHRS7, a short-chain fatty acid dehydrogenase/reductase (SDR), as conserved, 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Under oxidative stress, DHRS7 consumes NADP + to convert arachidonic acid (AA)-derived 5(S)-HETE into the inflammatory lipid 5-KETE, which activates leukocyte chemotaxis via the OXER1 receptor. While Dhrs7 acts as a NADPH-dependent 5-KETE sink in unstressed, healthy tissue, it promotes rapid, 5-KETE dependent leukocytic inflammation in wounded zebrafish skin. Thus, DHRS7 epitomizes an underappreciated mode of redox signalling-beyond classic SH oxidation-that leverages NADPH metabolism to generate or quench a paracrine lipid signal. Metabolic redox sensors like DHRS7 might be promising therapeutic targets in diseases characterized by disturbed redox balance.

DOI: https://doi.org/10.1101/2025.02.05.636725