HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth

Ameri, Kurosh; Jahangiri, Arman; Rajah, Anthony M.; Tormos, Kathryn V.; Nagarajan, R; Pekmezci, Melike; Nguyen, Vien; Wheeler, Matthew L.; Murphy, Michael P.; Sanders, Timothy A.; Jeffrey, Stefanie S.; Yeghiazarians, Yerem; Rinaudo, Paolo; Costello, J; Aghi, Manish K.; Maltepe, Emin

doi:10.1016/j.celrep.2015.01.020

Cited by 81 publications

(78 citation statements)

References 63 publications

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“…Nevertheless, others correlated HIGD1A activity with OXPHOS suppression (Ameri et al 2015). HIGD1A is regarded as a metabolic stress sensor with the ability to translocate from mitochondria to nucleus (Ameri et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Aglycemia keeps mitochondrial oxidative phosphorylation under hypoxic conditions in HepG2 cells

Plecitá–Hlavatá

Ježek

2015

J Bioenerg Biomembr

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Cancer cell bioenergetics, maintaining mixed aerobic glycolysis (Warburg phenotype) and oxidative phosphorylation (OXPHOS), is not fully elucidated. Hypoxia-dependent OXPHOS suppression determines aerobic glycolysis. To elucidate further details, we studied hypoxic adaptation (up to 72 h at 5 % oxygen) of hepatocellular carcinoma HepG2 cells. The key regulatory component, hypoxia-inducible factor (HIF)-1α (HIF-1α) was stabilized at 5 h in 5 % oxygen for all three studied regimens, i.e. in glycolytic cells at 5 mM or 25 mM glucose, or in aglycemic (OXPHOS) cells when glucose was replaced by galactose. However, the conventional HIF-mediated suppression of respiration was prevented at aglycemia, which correlated with a high proportion of unphosphorylated pyruvate dehydrogenase (PDH) at 5 % oxygen. Such a modified HIF response in OXPHOS cells, termed as a non-canonical one, contrasted to conventional respiration suppression down to 45 % or 43 %, observed in hypoxia-adapted glycolytic cells at 5 mM or 25 mM glucose, respectively. These hypoxic glycolytic cells had normally highly phosphorylated PDH and most likely utilized pyruvate by aminotransferase reaction of glutaminolysis to feed at least suppressed respiration. Also, glycolytic cells were rather resistant towards the staurosporine-induced apoptosis, whereas aglycemic (OXPHOS) HepG2 cells exhibited much higher susceptibility. We conclude that aglycemia modulates the hypoxic HIF signaling toward a non-canonical response that is unable to carry out complete PDH phosphorylation, allowing a high pyruvate input for OXPHOS from the elevated glycolysis, which together with ongoing glutaminolysis maintain a virtually unchanged respiration. Similar OXPHOS revival may explain distinct tumor sensitivity to chemotherapy and other pharmacological interventions.

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Section: Discussionmentioning

confidence: 99%

Aglycemia keeps mitochondrial oxidative phosphorylation under hypoxic conditions in HepG2 cells

Plecitá–Hlavatá

Ježek

2015

J Bioenerg Biomembr

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“…According to the literature, both events may facilitate Cc translocation to the cytoplasm during apoptosis (77). However, phosphorylation at Tyr48 hinders the proapoptotic activity of extramitochondrial Cc, similar to the function of HIGD1A protein in ischemia and tumorigenesis (78). Indeed, both HIGD1A and Y48pCMF Cc act as prosurvival proteins by preventing apoptotic caspase activation (Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48

Moreno‐Beltrán

Guerra‐Castellano

Díaz-Quintana

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of mitochondrial activity allows cells to adapt to changing conditions and to control oxidative stress, and its dysfunction can lead to hypoxia-dependent pathologies such as ischemia and cancer. Although cytochrome c phosphorylation—in particular, at tyrosine 48—is a key modulator of mitochondrial signaling, its action and molecular basis remain unknown. Here we mimic phosphorylation of cytochrome c by replacing tyrosine 48 with p-carboxy-methyl-l-phenylalanine (pCMF). The NMR structure of the resulting mutant reveals significant conformational shifts and enhanced dynamics around pCMF that could explain changes observed in its functionality: The phosphomimetic mutation impairs cytochrome c diffusion between respiratory complexes, enhances hemeprotein peroxidase and reactive oxygen species scavenging activities, and hinders caspase-dependent apoptosis. Our findings provide a framework to further investigate the modulation of mitochondrial activity by phosphorylated cytochrome c and to develop novel therapeutic approaches based on its prosurvival effects.

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“…HIGD1A suppresses oxidative phosphorylation, activates AMPK, and suppresses reactive oxygen species (ROS) production. Consequently, HIGD1A supports the survival of cancer cells under severely hypoxic conditions . The orphan nuclear receptor, NR2F1, plays a role in the maintenance of dormancy through SOX9, PARβ, and CDK inhibitors in HEp3 cells .…”

Section: Cellular Dormancymentioning

confidence: 99%

Dormancy in cancer

2019

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The idea of tumor dormancy originated from clinical findings that recurrence of cancer occurs several years or even several decades after surgical resection of the primary tumor. Tumor mass dormancy was proposed as a model, where there is equal balance between increases in the number of cancer cells by proliferation and decreases as a result of cell death. Tumor mass dormancy includes angiogenic dormancy and immune‐mediated dormancy. Another emerging type of tumor dormancy is cellular dormancy in which cancer cells are in a quiescent state. Cellular dormancy is induced by cues such as the extracellular matrix environment, metastatic niches, a hypoxic microenvironment, and endoplasmic reticulum stress. Even the oncogenic pathways, on which active cancer cells depend for survival and growth, are suppressed in the dormant state. As tumor dormancy is one of the mechanisms of resistance against various cancer therapies, targeting dormant cancer cells should be considered for future treatment strategies.

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HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth

Cited by 81 publications

References 63 publications

Aglycemia keeps mitochondrial oxidative phosphorylation under hypoxic conditions in HepG2 cells

Aglycemia keeps mitochondrial oxidative phosphorylation under hypoxic conditions in HepG2 cells

Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48

Dormancy in cancer

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