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Restriction of Aerobic Metabolism by Acquired or Innate Arylsulfatase B Deficiency: A New Approach to the Warburg Effect

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ABSTRACT

Aerobic respiration is required for optimal efficiency of metabolism in mammalian cells. Under circumstances when oxygen utilization is impaired, cells survive by anerobic metabolism. The malignant cell has cultivated the use of anerobic metabolism in an aerobic environment, the Warburg effect, but the explanation for this preference is not clear. This paper presents evidence that deficiency of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase), either innate or acquired, helps to explain the Warburg phenomenon. ARSB is the enzyme that removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate and dermatan sulfate. Previous reports indicated reduced ARSB activity in malignancy and replication of the effects of hypoxia by decline in ARSB. Hypoxia reduced ARSB activity, since molecular oxygen is needed for post-translational modification of ARSB. In this report, studies were performed in human HepG2 cells and in hepatocytes from ARSB-deficient and normal C57BL/6J control mice. Decline of ARSB, in the presence of oxygen, profoundly reduced the oxygen consumption rate and increased the extracellular acidification rate, indicating preference for aerobic glycolysis. Specific study findings indicate that decline in ARSB activity enhanced aerobic glycolysis and impaired normal redox processes, consistent with a critical role of ARSB and sulfate reduction in mammalian metabolism.

No MeSH data available.


Mitochondrial membrane potential and Complex 1 activity in ARSB- mice.(A) Mitochondrial membrane potential was measured in the HepG2 cells and shown to be significantly less when ARSB was silenced (n = 6; one-way ANOVA with Tukey-Kramer post-test). (B) Similarly, the mitochondrial membrane potential in the mitochondria from the ARSB- primary hepatocytes was significantly less than in hepatocytes from the C57BL/6J control mice (n = 6). (C) The activity of Complex 1 was determined by an NADH dehydrogenase activity assay which showed marked reduction of activity in the mitochondria of the HepG2 cells following ARSB silencing, compared to control (n = 6). (D) Graphical representation of the slope of the activity shows the significant difference following ARSB silencing. (E) Similarly, Complex 1 activity was markedly reduced in the crude mitochondrial fraction from ARSB- mouse hepatic tissue, compared to the value in the C57BL/6J (n = 6). (F) Graphical representation of the decline in Complex 1 activity of the ARSB- mouse hepatic tissue, compared to the control [ARSB = arylsulfatase B; ER = endoplasmic reticulum; MMP = mitochondrial membrane potential].
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f4: Mitochondrial membrane potential and Complex 1 activity in ARSB- mice.(A) Mitochondrial membrane potential was measured in the HepG2 cells and shown to be significantly less when ARSB was silenced (n = 6; one-way ANOVA with Tukey-Kramer post-test). (B) Similarly, the mitochondrial membrane potential in the mitochondria from the ARSB- primary hepatocytes was significantly less than in hepatocytes from the C57BL/6J control mice (n = 6). (C) The activity of Complex 1 was determined by an NADH dehydrogenase activity assay which showed marked reduction of activity in the mitochondria of the HepG2 cells following ARSB silencing, compared to control (n = 6). (D) Graphical representation of the slope of the activity shows the significant difference following ARSB silencing. (E) Similarly, Complex 1 activity was markedly reduced in the crude mitochondrial fraction from ARSB- mouse hepatic tissue, compared to the value in the C57BL/6J (n = 6). (F) Graphical representation of the decline in Complex 1 activity of the ARSB- mouse hepatic tissue, compared to the control [ARSB = arylsulfatase B; ER = endoplasmic reticulum; MMP = mitochondrial membrane potential].

Mentions: To assess the impact of decline in ARSB on the mitochondrial membrane, mitochondrial membrane potential (MMP) was measured by the J10 dye, in ARSB-silenced and control-silenced HepG2 cells (Fig. 4A) and in primary hepatocytes from ARSB- and control C57BL/6J mice (Fig. 4B). MMP was significantly less following ARSB siRNA, as compared to control values (p < 0.0001).


Restriction of Aerobic Metabolism by Acquired or Innate Arylsulfatase B Deficiency: A New Approach to the Warburg Effect
Mitochondrial membrane potential and Complex 1 activity in ARSB- mice.(A) Mitochondrial membrane potential was measured in the HepG2 cells and shown to be significantly less when ARSB was silenced (n = 6; one-way ANOVA with Tukey-Kramer post-test). (B) Similarly, the mitochondrial membrane potential in the mitochondria from the ARSB- primary hepatocytes was significantly less than in hepatocytes from the C57BL/6J control mice (n = 6). (C) The activity of Complex 1 was determined by an NADH dehydrogenase activity assay which showed marked reduction of activity in the mitochondria of the HepG2 cells following ARSB silencing, compared to control (n = 6). (D) Graphical representation of the slope of the activity shows the significant difference following ARSB silencing. (E) Similarly, Complex 1 activity was markedly reduced in the crude mitochondrial fraction from ARSB- mouse hepatic tissue, compared to the value in the C57BL/6J (n = 6). (F) Graphical representation of the decline in Complex 1 activity of the ARSB- mouse hepatic tissue, compared to the control [ARSB = arylsulfatase B; ER = endoplasmic reticulum; MMP = mitochondrial membrane potential].
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Related In: Results  -  Collection

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f4: Mitochondrial membrane potential and Complex 1 activity in ARSB- mice.(A) Mitochondrial membrane potential was measured in the HepG2 cells and shown to be significantly less when ARSB was silenced (n = 6; one-way ANOVA with Tukey-Kramer post-test). (B) Similarly, the mitochondrial membrane potential in the mitochondria from the ARSB- primary hepatocytes was significantly less than in hepatocytes from the C57BL/6J control mice (n = 6). (C) The activity of Complex 1 was determined by an NADH dehydrogenase activity assay which showed marked reduction of activity in the mitochondria of the HepG2 cells following ARSB silencing, compared to control (n = 6). (D) Graphical representation of the slope of the activity shows the significant difference following ARSB silencing. (E) Similarly, Complex 1 activity was markedly reduced in the crude mitochondrial fraction from ARSB- mouse hepatic tissue, compared to the value in the C57BL/6J (n = 6). (F) Graphical representation of the decline in Complex 1 activity of the ARSB- mouse hepatic tissue, compared to the control [ARSB = arylsulfatase B; ER = endoplasmic reticulum; MMP = mitochondrial membrane potential].
Mentions: To assess the impact of decline in ARSB on the mitochondrial membrane, mitochondrial membrane potential (MMP) was measured by the J10 dye, in ARSB-silenced and control-silenced HepG2 cells (Fig. 4A) and in primary hepatocytes from ARSB- and control C57BL/6J mice (Fig. 4B). MMP was significantly less following ARSB siRNA, as compared to control values (p < 0.0001).

View Article: PubMed Central - PubMed

ABSTRACT

Aerobic respiration is required for optimal efficiency of metabolism in mammalian cells. Under circumstances when oxygen utilization is impaired, cells survive by anerobic metabolism. The malignant cell has cultivated the use of anerobic metabolism in an aerobic environment, the Warburg effect, but the explanation for this preference is not clear. This paper presents evidence that deficiency of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase), either innate or acquired, helps to explain the Warburg phenomenon. ARSB is the enzyme that removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate and dermatan sulfate. Previous reports indicated reduced ARSB activity in malignancy and replication of the effects of hypoxia by decline in ARSB. Hypoxia reduced ARSB activity, since molecular oxygen is needed for post-translational modification of ARSB. In this report, studies were performed in human HepG2 cells and in hepatocytes from ARSB-deficient and normal C57BL/6J control mice. Decline of ARSB, in the presence of oxygen, profoundly reduced the oxygen consumption rate and increased the extracellular acidification rate, indicating preference for aerobic glycolysis. Specific study findings indicate that decline in ARSB activity enhanced aerobic glycolysis and impaired normal redox processes, consistent with a critical role of ARSB and sulfate reduction in mammalian metabolism.

No MeSH data available.