A Refined Analysis of Superoxide Production by Mitochondrial sn-Glycerol 3-Phosphate Dehydrogenase

Orr, Adam L.; Quinlan, Casey L.; Perevoshchikova, Irina V.; Brand, Martin D.

doi:10.1074/jbc.m112.397828

Cited by 149 publications

(124 citation statements)

References 58 publications

(88 reference statements)

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“…Despite its high oxidative capacity, the basal mitochondrial ROS production in heart is modest compared to skeletal muscle and brain [21]. This counterintuitive observation might be explained by the heart mitochondrial respiratory chain being normally tuned to high OXPHOS output with minimal basal ROS production.…”

Section: Ros and Heart: Dearth Precedes Destructionmentioning

confidence: 76%

The role of mitochondria in cardiac development and protection

Pohjoismäki

Goffart

2017

Free Radical Biology and Medicine

101

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Mitochondria are essential for the development as well as maintenance of the myocardium, the most energy consuming tissue in the human body. Mitochondria are not only a source of ATP energy but also generators of reactive oxygen species (ROS), that cause oxidative damage, but also regulate physiological processes such as the switch from hyperplastic to hypertrophic growth after birth. As excess ROS production and oxidative damage are associated with cardiac pathology, it is not surprising that much of the research focused on the deleterious aspects of free radicals. However, cardiomyocytes are naturally highly adapted against repeating oxidative insults, with evidence suggesting that moderate and acute ROS exposure has beneficial consequences for mitochondrial maintenance and cardiac health. Antioxidant defenses, mitochondrial quality control, mtDNA maintenance mechanisms as well as mitochondrial fusion and fission improve mitochondrial function and cardiomyocyte survival under stress conditions. As these adaptive processes can be induced, promoting mitohormesis or mitochondrial biogenesis using controlled ROS exposure could provide a promising strategy to increase cardiomyocyte survival and prevent pathological remodeling of the myocardium.

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Section: Ros and Heart: Dearth Precedes Destructionmentioning

confidence: 76%

The role of mitochondria in cardiac development and protection

Pohjoismäki

Goffart

2017

Free Radical Biology and Medicine

101

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“…Importantly, G3P-mediated mitochondrial energization can drive ROS production by RET or from mitochondrial G3P dehydrogenase (GPD2) itself (7,30). Moreover, GPD2 appears to have the capacity to produce ROS in the mitochondrial intermembrane space (30,41,45), as opposed to complex I, which produces superoxide in the mitochondrial matrix (12). This compartmentalization of ROS production is a plausible explanation for the sensitivity of UCP1-KO mitochondria to succinate-mediated ROS production, which drives superoxide production principally through complex I (12).…”

Section: Discussionmentioning

confidence: 99%

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

Kazak

Chouchani

Stavrovskaya

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

146

107

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Brown adipose tissue (BAT) mitochondria exhibit high oxidative capacity and abundant expression of both electron transport chain components and uncoupling protein 1 (UCP1). UCP1 dissipates the mitochondrial proton motive force (Δp) generated by the respiratory chain and increases thermogenesis. Here we find that in mice genetically lacking UCP1, cold-induced activation of metabolism triggers innate immune signaling and markers of cell death in BAT. Moreover, global proteomic analysis reveals that this cascade induced by UCP1 deletion is associated with a dramatic reduction in electron transport chain abundance. UCP1-deficient BAT mitochondria exhibit reduced mitochondrial calcium buffering capacity and are highly sensitive to mitochondrial permeability transition induced by reactive oxygen species (ROS) and calcium overload. This dysfunction depends on ROS production by reverse electron transport through mitochondrial complex I, and can be rescued by inhibition of electron transfer through complex I or pharmacologic depletion of ROS levels. Our findings indicate that the interscapular BAT of Ucp1 knockout mice exhibits mitochondrial disruptions that extend well beyond the deletion of UCP1 itself. This finding should be carefully considered when using this mouse model to examine the role of UCP1 in physiology.brown fat | mitochondria | ROS | UCP1 | electron transport chain U ncoupling protein 1 (UCP1) plays a role in acute adaptive thermogenesis in interscapular brown adipose tissue (BAT). UCP1 dissipates the mitochondrial protonmotive force (Δp) generated by the electron transport chain (ETC) and is important for thermal homeostasis in rodents and human infants (1, 2). Ucp1 orthologs are not limited to mammals, but are also expressed in ectothermic vertebrates (3) and protoendothermic mammals (4), suggesting that UCP1 may have an important role in biology beyond thermal control. For example, it is becoming increasingly evident that in specific respiratory states, UCP1 can reduce reactive oxygen species (ROS) levels in vitro (4-9). The mitochondrial ETC is a major source of ROS production in the cell, and ROS play important roles in physiology and pathophysiology (10-12). Reverse electron transport (RET) through mitochondrial complex I is a key mechanism by which ROS are generated in vivo (11, 13). Interestingly, RET relies critically on high Δp, whereas dissipation of Δp by UCP1 can lower ROS levels in isolated mitochondria (5-7).Thermogenic respiration in BAT is triggered by external stimuli that activate adrenergic signaling (14). Most notably, environmental cold induces the capacity for adrenergic-mediated BAT respiration in wild type (WT) animals, but only minimally in UCP1-KO animals (15, 16). It is understood that the respiratory response of BAT under these conditions is indicative of UCP1-mediated respiration; however, the rate of maximal chemically uncoupled oxygen consumption, an UCP1-independent parameter, is also lower in UCP1-KO adipocytes compared with WT (15, 16).Moreover, the basal respiratory rat...

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“…Most of the sites produce superoxide/H 2 O 2 exclusively to the matrix, so their relative contributions will not change substantially after correction. Importantly, however, ϳ50% of the superoxide/H 2 O 2 from sites III Qo and G Q is produced toward the cytosol and avoids matrix peroxidase scavenging (17,21). Therefore, the contribution of these sites becomes relatively smaller after this correction.…”

Section: Rates Of H 2 O 2 Production After Correction For Losses Of Hmentioning

confidence: 99%

“…1. In order of their maximum capacities, they are as follows: III Qo 4 in complex III (17); I Q (18,19) and II F (20) in complexes I and II; O F , P F , and B F in the 2-oxoglutarate, pyruvate, and branched-chain 2-oxoacid dehydrogenase complexes (16); G Q in mitochondrial glycerol phosphate dehydrogenase (21); I F in complex I (16); E F in ETF/ETF:Q oxidoreductase (22); and D Q in dihydroorotate dehydrogenase (23).…”

mentioning

confidence: 99%

Sites of Superoxide and Hydrogen Peroxide Production by Muscle Mitochondria Assessed ex Vivo under Conditions Mimicking Rest and Exercise

Gonçalves

Quinlan²,

Perevoshchikova

et al. 2015

Journal of Biological Chemistry

Self Cite

282

237

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Background: Ten mitochondrial sites of superoxide/H 2 O 2 generation are known, but their contributions in vivo are undefined. Results: We assessed their rates ex vivo in conditions mimicking rest and exercise. Conclusion: Sites I Q and II F generated half the signal at rest. During exercise, rates were lower, and site I F dominated. Significance: Contributing sites ex vivo probably reflect those in vivo.

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A Refined Analysis of Superoxide Production by Mitochondrial sn-Glycerol 3-Phosphate Dehydrogenase

Cited by 149 publications

References 58 publications

The role of mitochondria in cardiac development and protection

The role of mitochondria in cardiac development and protection

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

Sites of Superoxide and Hydrogen Peroxide Production by Muscle Mitochondria Assessed ex Vivo under Conditions Mimicking Rest and Exercise

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