An out-of-frame cytochromeb gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production

Rana, Michele; Coo, I.F.M. de; Díaz, Francisca; Smeets, Hubert; Moraes, Carlos T.

doi:10.1002/1531-8249(200011)48:5<774::aid-ana11>3.0.co;2-i

Cited by 113 publications

(41 citation statements)

References 34 publications

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“…In the latter study, a detailed metabolomics analysis using stable isotope tracing identified high levels of succinate primarily generated through oxidative glutamine metabolism. It is noteworthy that an undetectable level of cytochrome b was reported in the previous biochemical characterization of these cells, as expected for an out-of-frame deletion located 40 bp down from the initiator methionine codon [27]. Consequently, CIII assembly was severely impaired and led to significant H 2 O 2 overproduction, but no change in CII activity was reported [27].…”

Section: Discussionmentioning

confidence: 78%

Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III

Tropeano

Fiori

Carelli

et al. 2018

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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A marked stimulation of complex II enzymatic activity was detected in cybrids bearing a homoplasmic MTCYB microdeletion causing disruption of both the activity and the assembly of complex III, but not in cybrids harbouring another MTCYB mutation affecting only the complex III activity. Moreover, complex II stimulation was associated with SDHA subunit tyrosine phosphorylation. Despite the lack of detectable hydrogen peroxide production, up-regulation of the levels of mitochondrial antioxidant defenses revealed a significant redox unbalance. This effect was also supported by the finding that treatment with N-acetylcysteine dampened the complex II stimulation, SDHA subunit tyrosine phosphorylation, and levels of antioxidant enzymes. In the absence of complex III, the cellular amount of succinate, but not fumarate, was markedly increased, indicating that enhanced activity of complex II is hampered due to the blockage of respiratory electron flow. Thus, we propose that complex II phosphorylation and stimulation of its activity represent a molecular mechanism triggered by perturbation of mitochondrial redox homeostasis due to severe dysfunction of respiratory complexes. Depending on the site and nature of the damage, complex II stimulation can either bypass the energetic deficit as an efficient compensatory mechanism, or be ineffectual, leaving cells to rely on glycolysis for survival.

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Section: Discussionmentioning

confidence: 78%

Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III

Tropeano

Fiori

Carelli

et al. 2018

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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“…An out of frame cytochrome b gene deletion occurred in a patient with Parkinsonism was associated with increased free radical production [49]. A novel mitochondrial 12 SrRNA point mutation was found in a pedigree with Parkinsonism, deafness and neuropathy [50].…”

Section: Mitochondrial Dysfunction In Pdmentioning

confidence: 99%

“…Thus, two windows have been identified, one that occurs very rapidly (within 1 h) [47][48][49] and a second one that develops slowly (over days) [40]. A difference between these 2 windows is that neuroprotection in the first window is transient.…”

Section: Ischemiamentioning

confidence: 99%

“…In the past, most preconditioning studies in brain have suggested that several hours are required to develop the tolerant state. However, in recent studies we and others suggested that preconditioning with a rapid onset time course, similar to that in heart (within 1 h), can protect synaptic activity after anoxia in brain slices [41][42][43][44][45][46] and reduce histopathology after ischemia in intact brain [47][48][49][50][51].Thus, two windows have been identified, one that occurs very rapidly (within 1 h) [47][48][49] and a second one that develops slowly (over days) [40]. A difference between these 2 windows is that neuroprotection in the first window is transient.…”

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confidence: 92%

“…In contrast, when rats were preconditioned days prior to the 'test' ischemic insult, the neuroprotection was robust and long lasting [40,52]. IPC and mitochondrial protection in the first window Recent studies from this laboratory and others suggest that preconditioning from the first window can protect ischemic injury, as assessed by the release of lactic dehydrogenase (LDH) or by synaptic activity recovery after the test insults in cell cultures [53], brain slices [41][42][43][44][45][46] and reduce histopathology after ischemia in intact brain [47,[49][50][51]54]. However, protection only ensued if reperfusion was allowed to occur for 3 d but not beyond [47].…”

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confidence: 99%

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Perioperative Neuroprotection Symposium

Fiskum¹

2004

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Public reporting burden for this collection of information is estimated to average 1 hour par the data needed, and completing and reviewing this collection of information. Send conranls reducing this burden to Washington Headquarters Services. Directorate for Information Operations Management and Budget, Paperwork Reduction Protect (0704-01681. Washington, DC 20803Indudkig the «ma for reviewing instructions, searching existing data sources, gathering and maintaining tMs burden estimate or any other aspect of this ooHecMon of information, including suggestions for 1218 Jefferson Davis Highway, Suite 1204, Arttngton, VA 22202-4302, and to the Office of AGENCY USE ONLY (Leave blank) REPORT DATE June 2004 REPORT TYPE AND DATES COVERED Final Proceedings (13 Sep 03-22 May 04) TITLE AND SUBTITLE Perioperative Neuroprotection Symposium AUTHOR(S)Gary Fiskum, Ph.D. S. FUNDING NUMBERS DAMD17-03-1-0500 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)University of Maryland, Baltimore Baltimore, MD 21201 E-Mail: gfisk001@umaryland.edu PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSORING / MONITORING AGENCY REPORT NUMBER SUPPLEMENTARY NOTESOriginal contains color plates: ALL DTIC reproductions will be in black and white 12a. DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 12b. DISTRIBUTION CODE A-TRACT IMaiiliwyiH 200 VVwW)The Perioperative Neuroprotection Symposium was held on April 16-19 in Ft. Lauderdale, Fl. The meeting was attended by approximately 140 registrant». Twenty four invited speakers made presentations in five sessions. An additional 40 poster presentations were^available for discussion throughout the meeting. Each participant received a symposium abstract book that included mini-reviews from each of the speakers and the short abstracts from the posters. The speakers also submitted formal manuscripts for peer-reviewed publication.Five of the poster presenters were also invited to submit short research manuscripts. Mitochondria and Neuroprotection Symposium April [16][17][18][19] 2004 Albert Lester Lehninger February 17,1917-March4,1986 Albert Lehninger was born in Bridgeport, Connecticut and received a B.A. in English from Wesleyan University in 1939. He received his Ph.D. in Physiological Chemistry from the University of Wisconsin in 1942. Lehninger stayed on at the Univ. of Wisconsin as an Instructor until 1945, when he was appointed Assistant Professor of Biochemistry and Surgery at the University of Chicago. At this juncture he had published 11 research articles. From 1945From -1952, he published an additional 33 articles. These studies included the discovery that fatty acid oxidation, ketone body metabolism, and the TCA cycle occur in the mitochondrion, some of the first investigations employing isolation of this organelle (see e.g., JBC1949 and 1950). Thus, while Lehninger was a chemist at heart, he was one of the founding father...

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