Contact sites between inner and outer mitochondrial membrane

Biermans, W.; Bakker, Annette; Jacob, W.

doi:10.1016/0005-2728(90)90254-2

Cited by 59 publications

(19 citation statements)

References 10 publications

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“…The high immunolabeling intensity and the uniform distribution ofgold grains indicates that Mi-CK is indeed a main component of the crystalline material. This is further corroborated by the fact that CK enzyme histochemistry (13) performed on frozen sections, subsequently embedded for electron microscopy, revealed high enzyme activity in the crystal-bearing mitochondria of RR fibers (Fig. 2F), indicating that Mi-CK is still enzymatically active in the affected mitochondria.…”

Section: Resultssupporting

confidence: 52%

Mitochondrial creatine kinase: a major constituent of pathological inclusions seen in mitochondrial myopathies.

Stadhouders

Jap

Winkler

et al. 1994

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

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Overaccumulation of abnormally organized mitochondria in so-called "ragged-red" skeletal muscle fibers Is a morphological hallmark of mitochondrial myopathies, in particular of mitochondrial encephalomyopathies. Characteristic for the abnormal mitochondria is the occurrence of highly ordered crystallineImmuno-electron microscopy revealed that these inclusions react heavily with specific antibodies against mitochondrial creatine kinase (Mi-CK). Image processing of selected crystalline inclusions, sectioned along the crystallographic b, c planes, resulted in an averaged picture displaying an arrangement of regular, square-shaped particles with a central cavity. The overall appearance, dimensions, and symmetry of these bullding blocks are very reminiscent of single isolated Mi-CK octamers. Taking these findins together, it is concluded that Mi-CK oiamers indeed represent the major, if not the only, component of these mitochondrial inclusions.The mitochondrial myopathies in which a defect in mitochondrial metabolism is thought to be the primary cause of the disease are clinically, biochemically, and genetically a heterogeneous group of disorders (1-3). For example, biochemical analysis reveals that respiratory chain deficiencies can be absent or vary from isolated defects to combined defects of several complexes of the chain (4, 5). To a varying degree, respiratory chain defects have also been reported in the so-called "encephalomyopathies"-i.e., in chronic progressive external ophthalmoplegia (CPEO), in Kearns-Sayre syndrome, in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), and in MERRF [myoclonus epilepsy with ragged-red fibers (RR fibers)] syndrome. All of these diseases are characterized by the presence of RR fibers in muscle biopsy specimens (1, 2).Characteristic aspects of the pathology in the RR fibers are an accumulation of abnormal and enlarged mitochondria and the occurrence in these mitochondria of highly ordered crystal-like inclusions, often referred to as "railway-track" or "parking lot" inclusions, within their intermembrane spaces (6, 7).Using optical diffraction techniques on thin muscle biopsy sections, the mitochondrial inclusions were shown to be true crystals (8). Two distinct types of crystals, type I (Fig. 1A) and type II (Fig. 1B), can be distinguished on the basis of shape, size, pattern, unit cell dimension, specific location of the crystals in the mitochondrial intermembrane space, and occurrence in different muscle fiber types. Understanding the role of the crystals in relation to the patient's pathology, either in terms of causative dysfunction or of mitochondrial response to a disease, requires a detailed knowledge of their chemical composition. Therefore, the biochemical and immunological nature ofthese inclusions has been studied using proteolytic digestion, enzyme cytochemistry, and immunogold labeling techniques. In addition, image processing of selected areas of these crystalline inclusions was performed to obtain more detailed s...

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Section: Resultssupporting

confidence: 52%

Mitochondrial creatine kinase: a major constituent of pathological inclusions seen in mitochondrial myopathies.

Stadhouders

Jap

Winkler

et al. 1994

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

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“…The distribution of peripheral mitochondrial creatine kinase was analysed by immunological [4] and histochemical [6] electron microscopic techniques, and by removing unattached outer membrane with digitonin. Clusters of the creatine kinase, such as described for hexokinase, were found in the attachment points [4,6]. This non-random distribution of the two kinases agreed with the analysis of isolated mitochondrial contact sites.…”

Section: Introductionmentioning

confidence: 99%

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

et al. 1996

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In vitro incubation of isolated hexokinase isozyme I or isolated dimer of mitochondrial creatine kinase with the outer mitochondrial membrane pore led to high molecular weight complexes of enzyme oligomers. Similar complexes of hexokinase and mitochondrial creatine kinase could be extracted by 0.5% Triton X-100 from homogenates of rat brain. Hexokinase and creatine kinase complexes could be separated by subsequent chromatography on DEAE anion exchanger. The molecular weight, as determined by gel-permeation chromatography, was approximately 400 kDa for both complexes. The Mr suggested tetramers of hexokinase (monomer 100 kDa) and creatine kinase (active enzyme is a dimer of 80 kDa). The composition of the complexes was further characterised by specific antibodies. Besides either hexokinase or creatine kinase molecules the complexes contained porin and adenylate translocator. It was possible to incorporate the complexes into artificial bilayer membranes and to measure conductance in 1 M KCI. The incorporating channels had a high conductance of 6 nS that was asymmetrically voltage dependent. The complexes were also reconstituted in phospholipid vesicles that were loaded with ATP. Complex containing vesicles retained ATP while vesicles reconstituted with pure porin were leaky. The internal ATP could be used by creatine kinase and bexokinase in the complex to phosphorylate external creatine or glucose. This process was inhibited by atractyloside. The hexokinase complex containing vesicles were furthermore loaded with malate or ATP that was gradually released by addition of Ca 2+ between 100 and 600 IJNI. The liberation of malate or ATP by Ca 2+ could be inhibited by N-methylVal-4-cyclosporin, suggesting that the porin translocator complex constitutes the permeability transition pore. The results show the physiological existence of kinase porin translocator complexes at the mitochondrial surface. It is assumed that such complexes between inner and outer membrane components are the molecular basis of contact sites observed by electron microscopy. Kinase complex formation may serve three regulatory functions, firstly regulation of the kinase activity, secondly stimulation of oxidative phosphorylation and thirdly regulation of the permeability transition pore.

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“…Recently it has been shown that the mitochondrial creatine kinase is localized to contact sites between the inner and outer mitochondrial membrane (Biermans et al, 1989(Biermans et al, , 1990, and that the creatine kinase may have preferential access to mitochondrially generated ATP relative to extramitochondrial ATP (Erickson-Viitanaen et al, 1982;Brooks & Suelter, 1987;Kuznetsov et al, 1989). Creatine kinase can specifically induce contact sites (Rojo et al, 1991), the contact sites appear to affect the activity of creatine kinase (Erickson-Viitanaen et al, 1982;Brooks & Suelter, 1987) and the frequency of contact sites varies with metabolic state (Biermans et al, 1989(Biermans et al, , 1990.…”

mentioning

confidence: 99%

“…Creatine kinase can specifically induce contact sites (Rojo et al, 1991), the contact sites appear to affect the activity of creatine kinase (Erickson-Viitanaen et al, 1982;Brooks & Suelter, 1987) and the frequency of contact sites varies with metabolic state (Biermans et al, 1989(Biermans et al, , 1990. Similarly, hexokinase isoenzyme 1 has been found to be mainly located at contact sites (Wieler et al, 1985) and has preferential access to mitochondrially generated ATP relative to extramitochondrial ATP (Arora & Pendersen, 1988), but is bound to the outer membrane pore protein, porin (Fiek et al, 1982).…”

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confidence: 99%

Control of respiration and ATP synthesis in mammalian mitochondria and cells

Brown

1992

Biochemical Journal

563

308

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We have seen that there is no simple answer to the question ‘what controls respiration?’ The answer varies with (a) the size of the system examined (mitochondria, cell or organ), (b) the conditions (rate of ATP use, level of hormonal stimulation), and (c) the particular organ examined. Of the various theories of control of respiration outlined in the introduction the ideas of Chance & Williams (1955, 1956) give the basic mechanism of how respiration is regulated. Increased ATP usage can cause increased respiration and ATP synthesis by mass action in all the main tissues. Superimposed on this basic mechanism is calcium control of matrix dehydrogenases (at least in heart and liver), and possibly also of the respiratory chain (at least in liver) and ATP synthase (at least in heart). In many tissues calcium also stimulates ATP usage directly; thus calcium may stimulate energy metabolism at (at least) four possible sites, the importance of each regulation varying with tissue. Regulation of multiple sites may occur (from a teleological point of view) because: (a) energy metabolism is branched and thus proportionate regulation of branches is required in order to maintain constant fluxes to branches (e.g. to proton leak or different ATP uses); and/or (b) control over fluxes is shared by a number of reactions, so that large increases in flux requires stimulation at multiple sites because each site has relatively little control. Control may be distributed throughout energy metabolism, possibly due to the necessity of minimizing cell protein levels (see Brown, 1991). The idea that energy metabolism is regulated by energy charge (as proposed by Atkinson, 1968, 1977) is misleading in mammals. Neither mitochondrial ATP synthesis nor cellular ATP usage is a unique function of energy charge as AMP is not a significant regulator (see for example Erecinska et al., 1977). The near-equilibrium hypothesis of Klingenberg (1961) and Erecinska & Wilson (1982) is partially correct in that oxidative phosphorylation is often close to equilibrium (apart from cytochrome oxidase) and as a consequence respiration and ATP synthesis are mainly regulated by (a) the phosphorylation potential, and (b) the NADH/NAD+ ratio. However, oxidative phosphorylation is not always close to equilibrium, at least in isolated mitochondria, and relative proximity to equilibrium does not prevent the respiratory chain, the proton leak, the ATP synthase and ANC having significant control over the fluxes. Thus in some conditions respiration rate correlates better with [ADP] than with phosphorylation potential, and may be relatively insensitive to mitochondrial NADH/NAD+ ratio.(ABSTRACT TRUNCATED AT 400 WORDS)

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Contact sites between inner and outer mitochondrial membrane

Cited by 59 publications

References 10 publications

Mitochondrial creatine kinase: a major constituent of pathological inclusions seen in mitochondrial myopathies.

Mitochondrial creatine kinase: a major constituent of pathological inclusions seen in mitochondrial myopathies.

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

Control of respiration and ATP synthesis in mammalian mitochondria and cells

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