Aspects, mechanism, and biological relevance of mitochondrial protein nitration sustained by mitochondrial nitric oxide synthase

Elfering, Sarah; Haynes, Virginia; Traaseth, Nathaniel J.; Ettl, Adam; Giulivi, Cecilia R

doi:10.1152/ajpheart.00766.2003

Cited by 92 publications

(104 citation statements)

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“…When mitochondria are exposed to nitrating agents, the mitochondrial matrix, where PDHC is located, exhibits the greatest nitration compared to other mitochondrial fractions (i.e., outer membrane, inner membrane, and inter-membrane space) [46]. PDHC is closely associated with Complex I of the electron transport chain [47] where much of the …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Tyrosine nitration is involved in many postischemic modifications [55][56][57]. Examples of proteins susceptible to inactivation by tyrosine nitration include mitochondrial superoxide dismutase [58,59] and several enzymes involved in oxidative energy metabolism, including aconitase [60], glutamate dehydrogenase [46], α-ketoglutarate dehydrogenase [61], and PDHC [46]. Because PDHC and α-ketoglutarate dehydrogenase complex share similar reaction mechanisms and an identical polypeptide subunit (E3), it is not surprising that they are both sensitive to enzyme inhibition by tyrosine nitration.…”

Section: Discussionmentioning

confidence: 99%

“…3). Moreover, the E2 subunit of the PDHC was also identified as a target for nitration by Elfering et al when mitochondria were incubated under conditions of enhanced endogenous nitric oxide production [46]. PDHC is composed of multiple subunits with many different potential targets of peroxynitrite, indicating that several mechanisms of inactivation may be involved.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…The relative sensitivity of PDHC to tyrosine nitration after cerebral ischemia and reperfusion is at this juncture unknown. A proteomic analysis, such as those that have identified PDHC as a highly nitrated protein in other paradigms [46,52,53] would likely resolve this question.Several other laboratories have also reported postischemic impairment of PDHC activity. Decreased activity of the PDHC in the dorsolateral striatum differentiates this region from ischemia-resistant areas during early recirculation in a rat model of transient ischemia, providing additional evidence for a relationship between PDHC inactivation and selective neuronal cell death [8].…”

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Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

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The pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of pyruvate and represents the sole bridge between anaerobic and aerobic cerebral energy metabolism. Previous studies demonstrating loss of PDHC enzyme activity and immunoreactivity during reperfusion after cerebral ischemia suggest that oxidative modifications are involved. This study tested the hypothesis that hyperoxic reperfusion exacerbates loss of PDHC enzyme activity, possibly due to tyrosine nitration or S-nitrosation. We used a clinically relevant canine ventricular fibrillation cardiac arrest model in which, after resuscitation and ventilation on either 100% O 2 (hyperoxic) or 21-30% O 2 (normoxic), animals were sacrificed at 2 h reperfusion and the brains removed for enzyme activity and immunoreactivity measurements. Animals resuscitated under hyperoxic conditions exhibited decreased PDHC activity and elevated 3-nitrotyrosine immunoreactivity in the hippocampus but not the cortex, compared to nonischemic controls. These measures were unchanged in normoxic animals. In vitro exposure of purified PDHC to peroxynitrite resulted in a dose-dependent loss of activity and increased nitrotyrosine immunoreactivity. These results support the hypothesis that oxidative stress contributes to loss of hippocampal PDHC activity during cerebral ischemia and reperfusion and suggest that PDHC is a target of peroxynitrite. KeywordsMitochondria; Hyperoxia; Nitrotyrosine; Normoxia; Oxidative stress; Global ischemia; Selective vulnerability; Free radicals Global cerebral ischemia and reperfusion cause severe neurochemical alterations, including oxidative modifications to lipids, proteins, and DNA. These and other covalent modifications can impair enzyme activities, including those necessary for energy metabolism. Alterations in these enzyme activities can limit postischemic aerobic metabolism and cellular ATP regeneration, thereby contributing to the pathophysiology of delayed neuronal cell death [1][2][3][4]. One enzyme known to be targeted and inactivated by reactive oxygen species is the pyruvate dehydrogenase complex (PDHC) [5]. Effects of ischemia/reperfusion on the PDHC can be particularly devastating because this enzyme forms the bridge between glycolysis and the Krebs cycle and can be the rate-limiting step in aerobic cerebral energy metabolism. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2008 October 21. Published in final edited form as:Free Radic Biol Med. 2006 June 1; 40(11): 1960-1970. doi:10.1016/j.freeradbiomed.2006.01.022. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe PDHC is located exclusively in the mitochondrial matrix and catalyzes the oxidative decarboxylation of pyruvate to form NADH and acetyl coenzyme A-the primary form of carbon that enters the Krebs cycle in the adult brain. Several laboratories have shown that PDHC enzyme activity is lost during cerebral ischemia/reperfusion [6][7][8]. PDHC im...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

mentioning

confidence: 99%

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Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

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Peptide‐Functionalized Fluorescent Particles for In Situ Detection of Nitric Oxide via Peroxynitrite‐Mediated Nitration

Chang

Chow

Dismuke

et al. 2017

Adv Healthcare Materials

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Nitric oxide (NO) is a free radical signaling molecule that plays a crucial role in modulating physiological homeostasis across multiple biological systems. NO dysregulation is linked to the pathogenesis of multiple diseases; therefore, its quantification is important for understanding pathophysiological processes. The detection of NO is challenging, typically limited by its reactive nature and short half‐life. Additionally, the presence of interfering analytes and accessibility to biological fluids in the native tissues make the measurement technically challenging and often unreliable. Here, a bio‐inspired peptide‐based NO sensor is developed, which detects NO‐derived oxidants, predominately peroxynitrite‐mediated nitration of tyrosine residues. It is demonstrated that these peptide‐based NO sensors can detect peroxynitrite‐mediated nitration in response to physiological shear stress by endothelial cells in vitro. Using the peptide‐conjugated fluorescent particle immunoassay, peroxynitrite‐mediated nitration activity with a detection limit of ≈100 × 10−9 m is detected. This study envisions that the NO detection platform can be applied to a multitude of applications including monitoring of NO activity in healthy and diseased tissues, localized detection of NO production of specific cells, and cell‐based/therapeutic screening of peroxynitrite levels to monitor pronitroxidative stress in biological samples.

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Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis

Campbell

Ziabreva

Reeve

et al. 2010

Annals of Neurology

327

251

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Objective Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system. We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases.Methods Ninety-eight snap-frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long-range and real-time PCR and sequencing were used to identify and analyze respiratory-deficient neurons devoid of complex IV and with complex II activity.Results The density of respiratory-deficient neurons in SPMS was strikingly in excess of aged controls. The majority of respiratory-deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions. Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS. The respiratory-deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single-cell level. Furthermore, there were neurons lacking mtDNA-encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory-deficient neurons.Interpretation These findings provide evidence that neurons in MS are respiratory-deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation. We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS.

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Aspects, mechanism, and biological relevance of mitochondrial protein nitration sustained by mitochondrial nitric oxide synthase

Cited by 92 publications

References 56 publications

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Peptide‐Functionalized Fluorescent Particles for In Situ Detection of Nitric Oxide via Peroxynitrite‐Mediated Nitration

Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis

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