Medizinische Universität Graz - Research portal
Selected Publication:
Pilic, J.
Influence of Hexokinase 1 Rings on Mitochondrial Function During Energy Stress
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2024. pp. 110
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- Authors Med Uni Graz:
- Advisor:
- Graier Wolfgang
- Madreiter-Sokolowski Corina
- Malli Roland
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- Abstract:
- Metabolic enzymes can adapt during energy stress, but the mechanisms and consequences of these adaptations remain understudied. We discovered that hexokinase 1 (HK1), a key glycolytic enzyme, clusters into ring-like structures around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial constriction sites. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the clustering of HK1. Moreover, we found critical mutations that are critical for the formation of HK1-rings. Utilizing these mutations, we could show that HK1-rings keep mitochondria connected and rewire cellular metabolism during energy stress. Our findings highlight that HK1 is a robust energy stress sensor that regulates the shape, connectivity and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy stress-related pathologies. HK1 has been shown to interact with the voltage-dependent anion channel 1 (VDAC1), a crucial gatekeeper in the outer mitochondrial membrane that controls metabolic and energy homeostasis. The available methodological approaches fell short of accurate visualization of VDAC1 in living cells. To permit precise VDAC1 imaging, we utilized the tetracysteine (TC)-tag and visualized VDAC1 dynamics in living cells. TC-tagged VDAC1 had a cluster-like distribution on mitochondria. The majority of VDAC1-clusters were localized at ER-mitochondria contact sites. Notably, we did not observe apparent colocalization between VDAC1 and HK1 during glucose depletion. However, VDAC1 colocalized with BCL-2 Antagonist/Killer (BAK)-clusters upon apoptotic stimulation. Additionally, VDAC1 was found at mitochondrial fission sites. These findings highlight the suitability of the TC-tag for live-cell imaging of VDAC1, shedding light on the roles of VDAC1 in multiple cellular processes.