Mitochondrial Dysfunction Resulting from Loss of Cytochrome C Impairs Cellular Oxygen Sensing and Hypoxic HIF-alpha Activation

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2005 Aug 2

PMID 16054088

Citations 274

Authors

Kyle D Mansfield

Robert D Guzy

Yi Pan

Regina M Young

Timothy P Cash

Paul T Schumacker

M Celeste Simon

Affiliations

Soon will be listed here.

Abstract

While cellular responses to low oxygen (O(2)) or hypoxia have been studied extensively, the precise identity of mammalian cellular O(2) sensors remains controversial. Using murine embryonic cells lacking cytochrome c, and therefore mitochondrial activity, we show that mitochondrial reactive oxygen species (mtROS) are essential for proper O(2) sensing and subsequent HIF-1 alpha and HIF-2 alpha stabilization at 1.5% O(2). In the absence of this signal, HIF-alpha subunits continue to be degraded. Furthermore, exogenous treatment with H(2)O(2) or severe O(2) deprivation is sufficient to stabilize HIF-alpha even in the absence of cytochrome c and functional mitochondria. These results provide genetic evidence indicating that mtROS act upstream of prolyl hydroxylases in regulating HIF-1 alpha and HIF-2 alpha in this O(2)-sensing pathway.

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