期刊
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
卷 1797, 期 6-7, 页码 865-877出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbabio.2010.02.016
关键词
Mitochondrial membrane potential; Mild uncoupling; Oxidative phosphorylation; Reverse electron transport; Forward electron transport; Redox potential; Hypoxia; Oxidative stress
资金
- NHLBI NIH HHS [P01 HL081427, R01 HL091923-01A2, R01 HL101235, R37 HL054598-14, R37HL54598, P01 HL081427-05, R37 HL054598, P01HL081427, R01 HL091923] Funding Source: Medline
While it is generally accepted that mitochondrial reactive oxygen species (ROS) balance depends on the both rate of single electron reduction of O-2 to superoxide (O-2(center dot-) by the electron transport chain and the rate of scavenging by intracellular antioxidant pathways, considerable controversy exists regarding the conditions leading to oxidative stress in intact cells versus isolated mitochondria. Here, we postulate that mitochondria have been evolutionarily optimized to maximize energy output while keeping ROS overflow to a minimum by operating in an intermediate redox state. We show that at the extremes of reduction or oxidation of the redox couples involved in electron transport (NADH/NAD(+)) or ROS scavenging (NADPH/NADP(+), GSH/GSSG), respectively, ROS balance is lost. This results in a net overflow of ROS that increases as one moves farther away from the optimal redox potential. At more reduced mitochondrial redox potentials, ROS production exceeds scavenging, while under more oxidizing conditions (e.g., at higher workloads) antioxidant defenses can be compromised and eventually overwhelmed. Experimental support for this hypothesis is provided in both cardiomyocytes and in isolated mitochondria from guinea pig hearts. The model reconciles, within a single framework, observations that isolated mitochondria tend to display increased oxidative stress at high reduction potentials (and high mitochondrial membrane potential, Delta Psi(m)), whereas intact cardiac cells can display oxidative stress either when mitochondria become more uncoupled ( i.e., low Delta Psi(m)) or when mitochondria are maximally reduced (as in ischemia or hypoxia). The continuum described by the model has the potential to account for many disparate experimental observations and also provides a rationale for graded physiological ROS signaling at redox potentials near the minimum. (C) 2010 Elsevier B.V. All rights reserved.
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