Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Roberts, David J.; Miyamoto, Shigeki

doi:10.1038/cdd.2014.173

Cited by 386 publications

(384 citation statements)

References 176 publications

(265 reference statements)

Supporting

Mentioning

367

Contrasting

Unclassified

Order By: Relevance

“…Hk2 (Hexokinase 2) catalyses the phosphorylation of glucose, the rate-limiting first step of glycolysis and is known as a molecule involved in energy metabolism and cellular protection [34]. Hk2 transcripts were significantly down-regulated in HD hearts (Fig.…”

Section: Transcriptional Remodeling Of Genes Involved In the Synthesimentioning

confidence: 98%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of resynthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.Keywords: Huntington's disease, cardiomyopathy, arrhythmia, energy imbalance, catabolism of nucleotides, heart failure 3 SUMMARY Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related cardiomyopathy has been widely described in different mouse models, however there is little known about the source of the pathological remodelling in HD hearts. We found that contractile dysfunction in HD settings might be caused by components of cellular energy imbalance, changes in catabolism of adenine nucleotides, steady-state internal redox derangements and an activation of AMPK, leading to a shift in the cardiac substrate preference. These changes were accompanied by increased concentrations of adenine nucleotide catabolites (inosine, hypoxanthine, xanthine and uric acid) and uridine in both HD mouse models and HD patients' plasma. These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD. Our study explores a mechanism that might lead to HD-related cardiomyopathy and opens new avenues for therapeutic treatments in HD. HIGHLIGHTS• Heart dysfunction in HD is caused by the altered metabolism of nucleotides in vivo • Altered energy imbalances may lead to heart malfunction in HD in vivo• Increased lev...

show abstract

Section: Transcriptional Remodeling Of Genes Involved In the Synthesimentioning

confidence: 98%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

show abstract

“…Hypoxia stimulates the expression of hexokinase II (HK-II, also known as HK2), a hexokinase isoform that is upregulated in various tumors and is associated with higher tumor grade and mortality (Roberts and Miyamoto, 2015). HK-II binds to the OMM through its interaction with the voltage-dependent anion channel 1 (VDAC1), the major porin of OMM.…”

Section: Introductionmentioning

confidence: 99%

Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia

Mylonis

Kourti

Samiotaki

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

Hypoxia inducible factor-1 (HIF-1) is the main transcriptional activator of the cellular response to hypoxia and an important target of anticancer therapy. Phosphorylation by ERK1 and/or ERK2 (MAPK3 and MAPK1, respectively; hereafter ERK) stimulates the transcriptional activity of HIF-1α by inhibiting its CRM1 (XPO1)-dependent nuclear export. Here, we demonstrate that phosphorylation by ERK also regulates the association of HIF-1α with a so-far-unknown interaction partner identified as mortalin (also known as GRP75 and HSPA9), which mediates non-genomic involvement of HIF-1α in apoptosis. Mortalin binds specifically to HIF-1α that lacks modification by ERK, and the HIF-1α-mortalin complex is localized outside the nucleus. Under hypoxia, mortalin mediates targeting of unmodified HIF-1α to the outer mitochondrial membrane, as well as association with VDAC1 and hexokinase II, which promotes production of a C-terminally truncated active form of VDAC1, denoted VDAC1-ΔC, and protection from apoptosis when ERK is inactivated. Under normoxia, transcriptionally inactive forms of unmodified HIF-1α or its C-terminal domain alone are also targeted to mitochondria, stimulate production of VDAC1-ΔC and increase resistance to etoposide-or doxorubicin-induced apoptosis. These findings reveal an ERK-controlled, unconventional and anti-apoptotic function of HIF-1α that might serve as an early protective mechanism upon oxygen limitation and promote cancer cell resistance to chemotherapy.

show abstract

“…Phosphorylation-mediated regulation of mitochondrial HK-II (Roberts & Miyamoto 2015) is therefore a critical step to confer protection by AKT. Thus, the fact of highly diminished mitochondrial activity during diabetes may be attributed to the gain in PHLPP function and consequent inhibition of mitochondrial HK-II phosphorylation by suppressed AKT action.…”

Section: Phlpp Alters Mitochondrial Function During Insulin-resistantmentioning

confidence: 99%

“…Thus, an interesting signaling pathway links insulin signaling to mitochondria through translocation of AKT. Hexokinase II (HK-II), a glycolytic enzyme, is known to translocate to the mitochondria (Roberts & Miyamoto 2015) and its deficiency contributes to the altered sensitivity of diabetes to cardiovascular disorders. PHLPP behaves as a novel regulator of glucose metabolism by negatively regulating the AKT and S6K kinase activity, which are known molecular players of glucose metabolism .…”

Section: Phlpp Alters Mitochondrial Function During Insulin-resistantmentioning

confidence: 99%

PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

Mathur

Pandey

Kakkar

2017

Journal of Endocrinology

View full text Add to dashboard Cite

Progressive research in the past decade converges to the impact of PHLPP in regulating the cellular metabolism through PI3K/AKT inhibition. Aberrations in PKB/AKT signaling coordinates with impaired insulin secretion and insulin resistance, identified during T2D, obesity and cardiovascular disorders which brings in the relevance of PHLPPs in the metabolic paradigm. In this review, we discuss the impact of PHLPP isoforms in insulin signaling and its associated cellular events including mitochondrial dysfunction, DNA damage, autophagy and cell death. The article highlights the plausible molecular targets that share the role during insulin-resistant states, whose understanding can be extended into treatment responses to facilitate targeted drug discovery for T2D and allied metabolic syndromes.

show abstract

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Cited by 386 publications

References 176 publications

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia

PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

Contact Info

Product

Resources

About