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

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.


Related in: MedlinePlus

Ultrastructural characteristics and mitochondrial gene expression in hepatic tissue from ARSB- mice.(A) Transmission electron micrographs (EM) of a mitochondrion from the control C57BL/6J mouse liver shows intact mitochondrial membranes and extensive surrounding endoplasmic reticulum (orange arrow) (bar = 200 nm; original magnification = 103,000). (B) In contrast, mitochondrion from ARSB- mouse liver shows unusual central inclusions (yellow arrow), disruption of the surrounding endoplasmic reticulum (ER; green arrow), and discontinuity of the mitochondrial membranes (blue arrow) (bar = 200 nm). (C) EM shows marked disruption of the mitochondrial membranes (blue arrow) and prominent central inclusions (yellow arrow), as well as disarray of the surrounding ER (green arrow) (bar = 500 nm). (D) EM of control mouse hepatic tissue shows abundant mitochondria and endoplasmic reticulum (orange arrow), without opacification of the surrounding cytoplasm (bar = 2 μm; original magnification = 15,000). (E) The ARSB- mice mitochondria show frequent central inclusions (yellow arrow) and disruption of the mitochondrial membranes (blue arrow) (bar = 1 μm). (F) The ARSB- hepatic cells show extensive opacification of the surrounding cytoplasm, loss of ER (green arrow) and disrupted mitochondria (pink arrow) (bar = 1 μm). (G) mRNA levels of three mitochondrial genes were determined by QPCR. The genes porin, TFAM (Transcription Factor A, mitochondrial) and PGC (peroxisome proliferator-activated receptor-gamma coactivator)-1α were significantly reduced in hepatic tissue of ARSB  mice. [AF = ARSB- female; AM = ARSB- male; ARSB = arylsulfatase B; CF = control female; CM =  = control male; EM = electron micrograph; ER = endoplasmic reticulum; MMP = mitochondrial membrane potential; TEM = transmission electron microscopy]
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f5: Ultrastructural characteristics and mitochondrial gene expression in hepatic tissue from ARSB- mice.(A) Transmission electron micrographs (EM) of a mitochondrion from the control C57BL/6J mouse liver shows intact mitochondrial membranes and extensive surrounding endoplasmic reticulum (orange arrow) (bar = 200 nm; original magnification = 103,000). (B) In contrast, mitochondrion from ARSB- mouse liver shows unusual central inclusions (yellow arrow), disruption of the surrounding endoplasmic reticulum (ER; green arrow), and discontinuity of the mitochondrial membranes (blue arrow) (bar = 200 nm). (C) EM shows marked disruption of the mitochondrial membranes (blue arrow) and prominent central inclusions (yellow arrow), as well as disarray of the surrounding ER (green arrow) (bar = 500 nm). (D) EM of control mouse hepatic tissue shows abundant mitochondria and endoplasmic reticulum (orange arrow), without opacification of the surrounding cytoplasm (bar = 2 μm; original magnification = 15,000). (E) The ARSB- mice mitochondria show frequent central inclusions (yellow arrow) and disruption of the mitochondrial membranes (blue arrow) (bar = 1 μm). (F) The ARSB- hepatic cells show extensive opacification of the surrounding cytoplasm, loss of ER (green arrow) and disrupted mitochondria (pink arrow) (bar = 1 μm). (G) mRNA levels of three mitochondrial genes were determined by QPCR. The genes porin, TFAM (Transcription Factor A, mitochondrial) and PGC (peroxisome proliferator-activated receptor-gamma coactivator)-1α were significantly reduced in hepatic tissue of ARSB mice. [AF = ARSB- female; AM = ARSB- male; ARSB = arylsulfatase B; CF = control female; CM =  = control male; EM = electron micrograph; ER = endoplasmic reticulum; MMP = mitochondrial membrane potential; TEM = transmission electron microscopy]

Mentions: Transmission electron micrographs of hepatic tissue from ARSB- and control mice are presented in Fig. 5(A–F). The images demonstrate frequent disruption of the mitochondrial inner and outer membranes, accumulation of dense particles centrally in the mitochondrial matrix, and marked reduction and disarray of the endoplasmic reticulum in the ARSB -mouse hepatic tissue (Fig. 5B,C,E,F), compared to age-matched control (Fig. 5A,D). An overall increase in degraded mitochondria is apparent in some of the images of the ARSB- hepatic tissue (Fig. 5F), compared to the control (Fig. 5D). However, in other regions, the density of the mitochondria appears similar to the control (Fig. 5E).


Restriction of Aerobic Metabolism by Acquired or Innate Arylsulfatase B Deficiency: A New Approach to the Warburg Effect
Ultrastructural characteristics and mitochondrial gene expression in hepatic tissue from ARSB- mice.(A) Transmission electron micrographs (EM) of a mitochondrion from the control C57BL/6J mouse liver shows intact mitochondrial membranes and extensive surrounding endoplasmic reticulum (orange arrow) (bar = 200 nm; original magnification = 103,000). (B) In contrast, mitochondrion from ARSB- mouse liver shows unusual central inclusions (yellow arrow), disruption of the surrounding endoplasmic reticulum (ER; green arrow), and discontinuity of the mitochondrial membranes (blue arrow) (bar = 200 nm). (C) EM shows marked disruption of the mitochondrial membranes (blue arrow) and prominent central inclusions (yellow arrow), as well as disarray of the surrounding ER (green arrow) (bar = 500 nm). (D) EM of control mouse hepatic tissue shows abundant mitochondria and endoplasmic reticulum (orange arrow), without opacification of the surrounding cytoplasm (bar = 2 μm; original magnification = 15,000). (E) The ARSB- mice mitochondria show frequent central inclusions (yellow arrow) and disruption of the mitochondrial membranes (blue arrow) (bar = 1 μm). (F) The ARSB- hepatic cells show extensive opacification of the surrounding cytoplasm, loss of ER (green arrow) and disrupted mitochondria (pink arrow) (bar = 1 μm). (G) mRNA levels of three mitochondrial genes were determined by QPCR. The genes porin, TFAM (Transcription Factor A, mitochondrial) and PGC (peroxisome proliferator-activated receptor-gamma coactivator)-1α were significantly reduced in hepatic tissue of ARSB  mice. [AF = ARSB- female; AM = ARSB- male; ARSB = arylsulfatase B; CF = control female; CM =  = control male; EM = electron micrograph; ER = endoplasmic reticulum; MMP = mitochondrial membrane potential; TEM = transmission electron microscopy]
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Related In: Results  -  Collection

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f5: Ultrastructural characteristics and mitochondrial gene expression in hepatic tissue from ARSB- mice.(A) Transmission electron micrographs (EM) of a mitochondrion from the control C57BL/6J mouse liver shows intact mitochondrial membranes and extensive surrounding endoplasmic reticulum (orange arrow) (bar = 200 nm; original magnification = 103,000). (B) In contrast, mitochondrion from ARSB- mouse liver shows unusual central inclusions (yellow arrow), disruption of the surrounding endoplasmic reticulum (ER; green arrow), and discontinuity of the mitochondrial membranes (blue arrow) (bar = 200 nm). (C) EM shows marked disruption of the mitochondrial membranes (blue arrow) and prominent central inclusions (yellow arrow), as well as disarray of the surrounding ER (green arrow) (bar = 500 nm). (D) EM of control mouse hepatic tissue shows abundant mitochondria and endoplasmic reticulum (orange arrow), without opacification of the surrounding cytoplasm (bar = 2 μm; original magnification = 15,000). (E) The ARSB- mice mitochondria show frequent central inclusions (yellow arrow) and disruption of the mitochondrial membranes (blue arrow) (bar = 1 μm). (F) The ARSB- hepatic cells show extensive opacification of the surrounding cytoplasm, loss of ER (green arrow) and disrupted mitochondria (pink arrow) (bar = 1 μm). (G) mRNA levels of three mitochondrial genes were determined by QPCR. The genes porin, TFAM (Transcription Factor A, mitochondrial) and PGC (peroxisome proliferator-activated receptor-gamma coactivator)-1α were significantly reduced in hepatic tissue of ARSB mice. [AF = ARSB- female; AM = ARSB- male; ARSB = arylsulfatase B; CF = control female; CM =  = control male; EM = electron micrograph; ER = endoplasmic reticulum; MMP = mitochondrial membrane potential; TEM = transmission electron microscopy]
Mentions: Transmission electron micrographs of hepatic tissue from ARSB- and control mice are presented in Fig. 5(A–F). The images demonstrate frequent disruption of the mitochondrial inner and outer membranes, accumulation of dense particles centrally in the mitochondrial matrix, and marked reduction and disarray of the endoplasmic reticulum in the ARSB -mouse hepatic tissue (Fig. 5B,C,E,F), compared to age-matched control (Fig. 5A,D). An overall increase in degraded mitochondria is apparent in some of the images of the ARSB- hepatic tissue (Fig. 5F), compared to the control (Fig. 5D). However, in other regions, the density of the mitochondria appears similar to the control (Fig. 5E).

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.


Related in: MedlinePlus