Cross-linking ATP synthase complexes in vivo eliminates mitochondrial cristae

Gavin, Paul; Prescott, Mark; Luff, Susan E.; Devenish, Rodney J.

doi:10.1242/jcs.01074

Cited by 67 publications

(54 citation statements)

References 46 publications

(74 reference statements)

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“…Mitochondria often undergo ultrastructural remodeling to tailor energy output to meet the demands on the cell and their number can vary between cells of the same tissue [68][69][70][71]. The "megamitochondria" we observed have disruptions in their cristae architecture, a condition which was previously noted with cross-linking ATP synthase complexes [72,73]. A general trend in cells of older organisms is a decrease in number and increase in size of the mitochondrial population [70,74].…”

Section: Discussionsupporting

confidence: 52%

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Burke

et al. 2010

j ocul biol dis inform

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Impairment of mitochondria function and cellular antioxidant systems are linked to aging and neurodegenerative diseases. In the eye, the retinal pigment epithelium (RPE) is exposed to a highly oxidative environment that contributes to age-related visual dysfunction. Here, we examined changes in mitochondrial function in human RPE cells and sensitivity to oxidative stress with increased chronological age. Primary RPE cells from young (9-20)-, mid-age (48-60)-, and >60 (62-76)-year-old donors were grown to confluency and examined by electron microscopy and flow cytometry using several mitochondrial functional assessment tools. Susceptibility of RPE cells to H 2 O 2 toxicity was determined by lactate dehydrogenase and cytochrome c release, as well as propidium iodide staining. Reactive oxygen species, cytoplasmic Ca 2+ [Ca 2+ ] c , and mitochondrial Ca 2+ [Ca 2+ ] m levels were measured using 2′,7′-dichlorodihydrofluorescein diacetate, fluo-3/AM, and Rhod-2/AM, respectively, adenosine triphosphate (ATP) levels were measured by a luciferin/luciferase-based assay and mitochondrial membrane potential (ΔΨm) estimated using 5,5′,6,6′-tetrachloro 1,1′3,3′-tetraethylbenzimid azolocarbocyanine iodide. Expression of mitochondrial and antioxidant genes was determined by real-time polymerase chain reaction. RPE cells show greater sensitivity to oxidative stress, reduction in expression of mitochondrial heat shock protein 70, uncoupling protein 2, and superoxide dismutase 3, and greater expression of superoxide dismutase 2 levels with increased chronological age. Changes in mitochondrial number, size, shape, matrix density, cristae architecture, and membrane integrity were more prominent in samples obtained from >60 years old compared to midage and younger donors. These mitochondria abnormalities correlated with lower ATP levels, reduced ΔΨm, decreased [Ca 2+ ] c , and increased sequestration of [Ca 2+ ] m in cells with advanced aging. Our study provides evidence for mitochondrial decay, bioenergetic deficiency, weakened antioxidant defenses, and increased sensitivity of RPE cells to oxidative stress with advanced aging. Our findings suggest that with increased severity of mitochondrial decay and oxidative stress, RPE function may be altered in some individuals in a way that makes the retina more susceptible to age-related injury.

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Section: Discussionsupporting

confidence: 52%

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Burke

et al. 2010

j ocul biol dis inform

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“…F 1 F O ATP synthase was homogeneously distributed along the cristae membranes. The enrichment of F 1 F O ATP synthase in positively curved membrane parts of cristae was observed before (Parsons, 1963;Strauss et al, 2008;Bieling et al, 2010;TrutaFeles et al, 2010), and ATP synthase dimerization probably a main determinant of cristae shaping (Paumard et al, 2002;Gavin et al, 2004;Minauro-Sanmiguel et al, 2005;Strauss et al, 2008;Davies et al, 2012). Unfortunately, the limited degree of immunogold labeling does not render the explicit confirmation of F 1 F O ATP synthase dimers possible.…”

Section: Discussionmentioning

confidence: 96%

Restricted diffusion of OXPHOS complexes in dynamic mitochondria delays their exchange between cristae and engenders a transitory mosaic distribution

Wilkens

Kohl

Busch

2013

Journal of Cell Science

130

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SummaryMitochondria are involved in cellular energy supply, signaling and apoptosis. Their ability to fuse and divide provides functional and morphological flexibility and is a key feature in mitochondrial quality maintenance. To study the impact of mitochondrial fusion/fission on the reorganization of inner membrane proteins, oxidative phosphorylation (OXPHOS) complexes in mitochondria of different HeLa cells were tagged with fluorescent proteins (GFP and DsRed-HA), and cells were fused by polyethylene glycol treatment. Redistribution of the tagged OXPHOS complexes was then followed by means of immunoelectron microscopy, two color super-resolution fluorescence microscopy and single molecule tracking. In contrast to outer membrane and matrix proteins, which mix quickly and homogeneously upon mitochondrial fusion, the mixing of inner membrane proteins was decelerated. Our data suggest that the composition of cristae is preserved during fusion of mitochondria and that cristae with mixed OXPHOS complexes are only slowly and successively formed by restricted diffusion of inner membrane proteins into existing cristae. The resulting transitory mosaic composition of the inner mitochondrial membrane illuminates mitochondrial heterogeneity and potentially is linked to local differences in function and membrane potential.

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“…mitochondrial DNA propagation/expression, remain unaffected in these mutant strains. An alternative point of view suggests that the ATP synthase in some way regulates cristae formation, a question that is currently being studied by several laboratories (47)(48)(49)(50)(51). A link between ATP synthase and cristae biogenesis was first suggested by Allen et al (52), based on electron microscopy analyses of Paramecium multimicronucleatum mitochondria.…”

Section: Ultrastructural and Immunocytochemical Analyses Of The ⌬Fmc1mentioning

confidence: 99%

“…In favor of this hypothesis, it was found that loss of ATP synthase subunit e or g, both of which appear to be specifically involved in the enzyme dimerization in yeast (54), results in abnormal mitochondrial morphologies characterized by numerous digitations and onion-like structures that correspond to an uncontrolled biogenesis and/or folding of the inner membrane (47). Moreover, a recent report from the Devenish laboratory (49) shows that the correct arrangement of F 1 F O -ATP synthase complexes within the inner membrane is crucial for the genesis and/or maintenance of mitochondrial cristae and morphology. Our examination, at the cellular level, of yeast mutants that fail to assemble the ␣ 3 ␤ 3 oligomer reinforces the notion that the ATP synthase is a key determinant in the biogenesis of the inner membrane.…”

Section: Ultrastructural and Immunocytochemical Analyses Of The ⌬Fmc1mentioning

confidence: 99%

Failure to Assemble the α3 β3 Subcomplex of the ATP Synthase Leads to Accumulation of the α and β Subunits within Inclusion Bodies and the Loss of Mitochondrial Cristae in Saccharomyces cerevisiae

Lefebvre-Legendre

Salin

Schaeffer

et al. 2005

Journal of Biological Chemistry

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The F 1 component of mitochondrial ATP synthase is an oligomeric assembly of five different subunits, ␣, ␤, ␥, ␦, and ⑀. In terms of mass, the bulk of the structure (ϳ90%) is provided by the ␣ and ␤ subunits, which form an (␣ ␤) 3 hexamer with adenine nucleotide binding sites at the ␣/␤ interfaces. We report here ultrastructural and immunocytochemical analyses of yeast mutants that are unable to form the ␣ 3 ␤ 3 oligomer, either because the ␣ or the ␤ subunit is missing or because the cells are deficient for proteins that mediate F 1 assembly (e.g. Atp11p, Atp12p, or Fmc1p). The F 1 ␣ and ␤ subunits of such mutant strains are detected within large electron-dense particles in the mitochondrial matrix. The composition of the aggregated species is principally full-length F 1 ␣ and/or ␤ subunit protein that has been processed to remove the amino-terminal targeting peptide. To our knowledge this is the first demonstration of mitochondrial inclusion bodies that are formed largely of one particular protein species. We also show that yeast mutants lacking the ␣ 3 ␤ 3 oligomer are devoid of mitochondrial cristae and are severely deficient for respiratory complexes III and IV. These observations are in accord with other studies in the literature that have pointed to a central role for the ATP synthase in biogenesis of the mitochondrial inner membrane.

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Cross-linking ATP synthase complexes in vivo eliminates mitochondrial cristae

Cited by 67 publications

References 46 publications

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Restricted diffusion of OXPHOS complexes in dynamic mitochondria delays their exchange between cristae and engenders a transitory mosaic distribution

Failure to Assemble the α3 β3 Subcomplex of the ATP Synthase Leads to Accumulation of the α and β Subunits within Inclusion Bodies and the Loss of Mitochondrial Cristae in Saccharomyces cerevisiae

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