Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate

Qing Yao, Mohd Parvez Khan, Christophe Merceron, Edward L. LaGory, Zachary Tata, Laura Mangiavini, Jiarui Hu, Krishna Vemulapalli, Navdeep Chandel, Amato J. Giaccia, Ernestina Schipani*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Oxygen (O2) is both an indispensable metabolic substrate and a regulatory signal that controls the activity of Hypoxia-Inducible Factor 1α (Hif1a), a mediator of the cellular adaptation to low O2 tension (hypoxia). Hypoxic cells require Hif1a to survive. Additionally, Hif1a is an inhibitor of mitochondrial respiration. Hence, we hypothesized that enhancing mitochondrial respiration is detrimental to the survival of hypoxic cells in vivo. We tested this hypothesis in the fetal growth plate, which is hypoxic. Our findings show that mitochondrial respiration is dispensable for survival of growth plate chondrocytes. Furthermore, its impairment prevents the extreme hypoxia and the massive chondrocyte death observed in growth plates lacking Hif1a. Consequently, augmenting mitochondrial respiration affects the survival of hypoxic chondrocytes by, at least in part, increasing intracellular hypoxia. We thus propose that partial suppression of mitochondrial respiration is crucial during development to protect the tissues that are physiologically hypoxic from lethal intracellular anoxia. The fetal growth plate is a hypoxic structure that gives rise to most of the skeleton. It is formed by cells known as chondrocytes. Yao et al. now show that impairment of mitochondrial respiration and, thus, oxygen consumption are crucial for the survival of hypoxic chondrocytes during fetal development.

Original languageEnglish (US)
Pages (from-to)748-763.e7
JournalDevelopmental Cell
Volume49
Issue number5
DOIs
StatePublished - Jun 3 2019

Fingerprint

Growth Plate
Fetal Development
Chondrocytes
Respiration
Cells
Oxygen
Hypoxia-Inducible Factor 1
Tissue
Skeleton
Oxygen Consumption
Hypoxia
Cell Survival
Substrates

Keywords

  • HIF
  • TFAM
  • cell death
  • chondrocyte
  • fetal development
  • glycolysis
  • growth plate
  • hypoxia
  • mitochondria
  • mitochondrial respiration

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

Cite this

Yao, Q., Khan, M. P., Merceron, C., LaGory, E. L., Tata, Z., Mangiavini, L., ... Schipani, E. (2019). Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate. Developmental Cell, 49(5), 748-763.e7. https://doi.org/10.1016/j.devcel.2019.04.029
Yao, Qing ; Khan, Mohd Parvez ; Merceron, Christophe ; LaGory, Edward L. ; Tata, Zachary ; Mangiavini, Laura ; Hu, Jiarui ; Vemulapalli, Krishna ; Chandel, Navdeep ; Giaccia, Amato J. ; Schipani, Ernestina. / Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate. In: Developmental Cell. 2019 ; Vol. 49, No. 5. pp. 748-763.e7.
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abstract = "Oxygen (O2) is both an indispensable metabolic substrate and a regulatory signal that controls the activity of Hypoxia-Inducible Factor 1α (Hif1a), a mediator of the cellular adaptation to low O2 tension (hypoxia). Hypoxic cells require Hif1a to survive. Additionally, Hif1a is an inhibitor of mitochondrial respiration. Hence, we hypothesized that enhancing mitochondrial respiration is detrimental to the survival of hypoxic cells in vivo. We tested this hypothesis in the fetal growth plate, which is hypoxic. Our findings show that mitochondrial respiration is dispensable for survival of growth plate chondrocytes. Furthermore, its impairment prevents the extreme hypoxia and the massive chondrocyte death observed in growth plates lacking Hif1a. Consequently, augmenting mitochondrial respiration affects the survival of hypoxic chondrocytes by, at least in part, increasing intracellular hypoxia. We thus propose that partial suppression of mitochondrial respiration is crucial during development to protect the tissues that are physiologically hypoxic from lethal intracellular anoxia. The fetal growth plate is a hypoxic structure that gives rise to most of the skeleton. It is formed by cells known as chondrocytes. Yao et al. now show that impairment of mitochondrial respiration and, thus, oxygen consumption are crucial for the survival of hypoxic chondrocytes during fetal development.",
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Yao, Q, Khan, MP, Merceron, C, LaGory, EL, Tata, Z, Mangiavini, L, Hu, J, Vemulapalli, K, Chandel, N, Giaccia, AJ & Schipani, E 2019, 'Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate', Developmental Cell, vol. 49, no. 5, pp. 748-763.e7. https://doi.org/10.1016/j.devcel.2019.04.029

Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate. / Yao, Qing; Khan, Mohd Parvez; Merceron, Christophe; LaGory, Edward L.; Tata, Zachary; Mangiavini, Laura; Hu, Jiarui; Vemulapalli, Krishna; Chandel, Navdeep; Giaccia, Amato J.; Schipani, Ernestina.

In: Developmental Cell, Vol. 49, No. 5, 03.06.2019, p. 748-763.e7.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate

AU - Yao, Qing

AU - Khan, Mohd Parvez

AU - Merceron, Christophe

AU - LaGory, Edward L.

AU - Tata, Zachary

AU - Mangiavini, Laura

AU - Hu, Jiarui

AU - Vemulapalli, Krishna

AU - Chandel, Navdeep

AU - Giaccia, Amato J.

AU - Schipani, Ernestina

PY - 2019/6/3

Y1 - 2019/6/3

N2 - Oxygen (O2) is both an indispensable metabolic substrate and a regulatory signal that controls the activity of Hypoxia-Inducible Factor 1α (Hif1a), a mediator of the cellular adaptation to low O2 tension (hypoxia). Hypoxic cells require Hif1a to survive. Additionally, Hif1a is an inhibitor of mitochondrial respiration. Hence, we hypothesized that enhancing mitochondrial respiration is detrimental to the survival of hypoxic cells in vivo. We tested this hypothesis in the fetal growth plate, which is hypoxic. Our findings show that mitochondrial respiration is dispensable for survival of growth plate chondrocytes. Furthermore, its impairment prevents the extreme hypoxia and the massive chondrocyte death observed in growth plates lacking Hif1a. Consequently, augmenting mitochondrial respiration affects the survival of hypoxic chondrocytes by, at least in part, increasing intracellular hypoxia. We thus propose that partial suppression of mitochondrial respiration is crucial during development to protect the tissues that are physiologically hypoxic from lethal intracellular anoxia. The fetal growth plate is a hypoxic structure that gives rise to most of the skeleton. It is formed by cells known as chondrocytes. Yao et al. now show that impairment of mitochondrial respiration and, thus, oxygen consumption are crucial for the survival of hypoxic chondrocytes during fetal development.

AB - Oxygen (O2) is both an indispensable metabolic substrate and a regulatory signal that controls the activity of Hypoxia-Inducible Factor 1α (Hif1a), a mediator of the cellular adaptation to low O2 tension (hypoxia). Hypoxic cells require Hif1a to survive. Additionally, Hif1a is an inhibitor of mitochondrial respiration. Hence, we hypothesized that enhancing mitochondrial respiration is detrimental to the survival of hypoxic cells in vivo. We tested this hypothesis in the fetal growth plate, which is hypoxic. Our findings show that mitochondrial respiration is dispensable for survival of growth plate chondrocytes. Furthermore, its impairment prevents the extreme hypoxia and the massive chondrocyte death observed in growth plates lacking Hif1a. Consequently, augmenting mitochondrial respiration affects the survival of hypoxic chondrocytes by, at least in part, increasing intracellular hypoxia. We thus propose that partial suppression of mitochondrial respiration is crucial during development to protect the tissues that are physiologically hypoxic from lethal intracellular anoxia. The fetal growth plate is a hypoxic structure that gives rise to most of the skeleton. It is formed by cells known as chondrocytes. Yao et al. now show that impairment of mitochondrial respiration and, thus, oxygen consumption are crucial for the survival of hypoxic chondrocytes during fetal development.

KW - HIF

KW - TFAM

KW - cell death

KW - chondrocyte

KW - fetal development

KW - glycolysis

KW - growth plate

KW - hypoxia

KW - mitochondria

KW - mitochondrial respiration

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U2 - 10.1016/j.devcel.2019.04.029

DO - 10.1016/j.devcel.2019.04.029

M3 - Article

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JO - Developmental Cell

JF - Developmental Cell

SN - 1534-5807

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