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  • 1
    Online Resource
    Online Resource
    Mitochondrial network complexity and pathological decrease in complex I activity are tightly correlated in isolated human complex I deficiency
    American Physiological Society ; 2005
    In:  American Journal of Physiology-Cell Physiology Vol. 289, No. 4 ( 2005-10), p. C881-C890
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 289, No. 4 ( 2005-10), p. C881-C890
    Abstract: Complex I (NADH:ubiquinone oxidoreductase) is the largest multisubunit assembly of the oxidative phosphorylation system, and its malfunction is associated with a wide variety of clinical syndromes ranging from highly progressive, often early lethal, encephalopathies to neurodegenerative disorders in adult life. The changes in mitochondrial structure and function that are at the basis of the clinical symptoms are poorly understood. Video-rate confocal microscopy of cells pulse-loaded with mitochondria-specific rhodamine 123 followed by automated analysis of form factor (combined measure of length and degree of branching), aspect ratio (measure of length), and number of revealed marked differences between primary cultures of skin fibroblasts from 13 patients with an isolated complex I deficiency. These differences were independent of the affected subunit, but plotting of the activity of complex I, normalized to that of complex IV, against the ratio of either form factor or aspect ratio to number revealed a linear relationship. Relatively small reductions in activity appeared to be associated with an increase in form factor and never with a decrease in number, whereas relatively large reductions occurred in association with a decrease in form factor and/or an increase in number. These results demonstrate that complex I activity and mitochondrial structure are tightly coupled in human isolated complex I deficiency. To further prove the relationship between aberrations in mitochondrial morphology and pathological condition, fibroblasts from two patients with a different mutation but a highly fragmented mitochondrial phenotype were fused. Full restoration of the mitochondrial network demonstrated that this change in mitochondrial morphology was indeed associated with human complex I deficiency.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00104.2005
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2005
    detail.hit.zdb_id: 1477334-X
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  • 2
    Online Resource
    Online Resource
    Inhibition of complex I of the electron transport chain causes O 2 − ·-mediated mitochondrial outgrowth
    American Physiological Society ; 2005
    In:  American Journal of Physiology-Cell Physiology Vol. 288, No. 6 ( 2005-06), p. C1440-C1450
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 288, No. 6 ( 2005-06), p. C1440-C1450
    Abstract: Recent evidence indicates that oxidative stress is central to the pathogenesis of a wide variety of degenerative diseases, aging, and cancer. Oxidative stress occurs when the delicate balance between production and detoxification of reactive oxygen species is disturbed. Mammalian cells respond to this condition in several ways, among which is a change in mitochondrial morphology. In the present study, we have used rotenone, an inhibitor of complex I of the respiratory chain, which is thought to increase mitochondrial O 2 − · production, and mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to investigate the relationship between mitochondrial O 2 − · production and morphology in human skin fibroblasts. Video-rate confocal microscopy of cells pulse loaded with the mitochondria-specific cation rhodamine 123, followed by automated analysis of mitochondrial morphology, revealed that chronic rotenone treatment (100 nM, 72 h) significantly increased mitochondrial length and branching without changing the number of mitochondria per cell. In addition, this treatment caused a twofold increase in lipid peroxidation as determined with C11-BODIPY 581/591 . Finally, digital imaging microscopy of cells loaded with hydroethidine, which is oxidized by O 2 − · to yield fluorescent ethidium, revealed that chronic rotenone treatment caused a twofold increase in the rate of O 2 − · production. MitoQ (10 nM, 72 h) did not interfere with rotenone-induced ethidium formation but abolished rotenone-induced outgrowth and lipid peroxidation. These findings show that increased mitochondrial O 2 − · production as a consequence of, for instance, complex I inhibition leads to mitochondrial outgrowth and that MitoQ acts downstream of this O 2 − · to prevent alterations in mitochondrial morphology.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00607.2004
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2005
    detail.hit.zdb_id: 1477334-X
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  • 3
    Online Resource
    Online Resource
    Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Cell Physiology Vol. 293, No. 1 ( 2007-07), p. C22-C29
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 293, No. 1 ( 2007-07), p. C22-C29
    Abstract: Malfunction of NADH:ubiquinone oxidoreductase or complex I (CI), the first and largest complex of the mitochondrial oxidative phosphorylation system, has been implicated in a wide variety of human disorders. To demonstrate a quantitative relationship between CI amount and activity and mitochondrial shape and cellular reactive oxygen species (ROS) levels, we recently combined native electrophoresis and confocal and video microscopy of dermal fibroblasts of healthy control subjects and children with isolated CI deficiency. Individual mitochondria appeared fragmented and/or less branched in patient fibroblasts with a severely reduced CI amount and activity (class I), whereas patient cells in which these latter parameters were only moderately reduced displayed a normal mitochondrial morphology (class II). Moreover, cellular ROS levels were significantly more increased in class I compared with class II cells. We propose a mechanism in which a mutation-induced decrease in the cellular amount and activity of CI leads to enhanced ROS levels, which, in turn, induce mitochondrial fragmentation when not appropriately counterbalanced by the cell's antioxidant defense systems.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00194.2006
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477334-X
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  • 4
    Online Resource
    Online Resource
    Simultaneous quantification of oxidative stress and cell spreading using 5-(and-6)-chloromethyl-2′,7′-dichlorofluorescein
    Wiley ; 2006
    In:  Cytometry Part A Vol. 69A, No. 12 ( 2006-12-01), p. 1184-1192
    Details
    In: Cytometry Part A, Wiley, Vol. 69A, No. 12 ( 2006-12-01), p. 1184-1192
    Type of Medium: Online Resource
    ISSN: 1552-4922 , 1552-4930
    URL: Issue
    URL: Journal
    URL: Article
    DOI: 10.1002/cyto.a.v69a:12
    DOI: 10.1002/(ISSN)1552-4930
    DOI: 10.1002/cyto.a.20348
    Language: English
    Publisher: Wiley
    Publication Date: 2006
    detail.hit.zdb_id: 2180639-1
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  • 5
    Online Resource
    Online Resource
    Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria
    American Physiological Society ; 2008
    In:  American Journal of Physiology-Cell Physiology Vol. 294, No. 5 ( 2008-05), p. C1124-C1132
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 294, No. 5 ( 2008-05), p. C1124-C1132
    Abstract: Mitochondria continuously change shape, position, and matrix configuration for optimal metabolite exchange. It is well established that changes in mitochondrial metabolism influence mitochondrial shape and matrix configuration. We demonstrated previously that inhibition of mitochondrial complex I (CI or NADH:ubiquinone oxidoreductase) by rotenone accelerated matrix protein diffusion and decreased the fraction and velocity of moving mitochondria. In the present study, we investigated the relationship between inherited CI deficiency, mitochondrial shape, mobility, and matrix protein diffusion. To this end, we analyzed fibroblasts of two children that represented opposite extremes in a cohort of 16 patients, with respect to their residual CI activity and mitochondrial shape. Fluorescence correlation spectroscopy (FCS) revealed no relationship between residual CI activity, mitochondrial shape, the fraction of moving mitochondria, their velocity, and the rate of matrix-targeted enhanced yellow fluorescent protein (mitoEYFP) diffusion. However, mitochondrial velocity and matrix protein diffusion in moving mitochondria were two to three times higher in patient cells than in control cells. Nocodazole inhibited mitochondrial movement without altering matrix EYFP diffusion, suggesting that both activities are mutually independent. Unexpectedly, electron microscopy analysis revealed no differences in mitochondrial ultrastructure between control and patient cells. It is discussed that the matrix of a moving mitochondrion in the CI-deficient state becomes less dense, allowing faster metabolite diffusion, and that fibroblasts of CI-deficient patients become more glycolytic, allowing a higher mitochondrial velocity.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00079.2008
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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