Characterization and metabolic function of mitochondrial contact sites

Brdiczka, Dieter; Bücheler, Klaus; Kottke, Matthias; Adams, Volker; Nalam, Vijaya Kumar

doi:10.1016/0005-2728(90)90256-4

Cited by 33 publications

(15 citation statements)

References 27 publications

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“…How could mtHK inhibit apoptosis? As indicated above mtHKs are associated with the OMM and HKI, and possibly HKII, also interact with VDAC, which is located at the contact sites between the OMM and the inner mitochondrial membrane (IMM) (1,6,7). This association affords mtHK "privileged access" to mitochondrial ATP, facilitates direct coupling between glucose phosphorylation and oxidative phosphorylation via ADP-ATP exchange across the mitochondrial membranes, and may provide kinetic advantages to mtHK (reviewed in references 38 and 39).…”

Section: Discussionmentioning

confidence: 96%

Akt Inhibits Apoptosis Downstream of BID Cleavage via a Glucose-Dependent Mechanism Involving Mitochondrial Hexokinases

Majewski¹,

Nogueira²,

Robey

et al. 2004

Molecular and Cellular Biology

272

198

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The serine/threonine kinase Akt/protein kinase B inhibits apoptosis induced by a variety of stimuli, including overexpression or activation of proapoptotic Bcl-2 family members. The precise mechanisms by which Akt prevents apoptosis are not completely understood, but Akt may function to maintain mitochondrial integrity, thereby preventing cytochrome c release following an apoptotic insult. This effect may be mediated, in part, via promotion of physical and functional interactions between mitochondria and hexokinases. Here we show that growth factor deprivation induced proteolytic cleavage of the proapoptotic Bcl-2 family member BID to yield its active truncated form, tBID. Activated Akt inhibited mitochondrial cytochrome c release and apoptosis following BID cleavage. Akt also antagonized tBID-mediated BAX activation and mitochondrial BAK oligomerization, two downstream events thought to be critical for tBID-induced apoptosis. Glucose deprivation, which impaired the ability of Akt to maintain mitochondrion-hexokinase association, prevented Akt from inhibiting BID-mediated apoptosis. Interestingly, tBID independently elicited dissociation of hexokinases from mitochondria, an effect that was antagonized by activated Akt. Ectopic expression of the amino-terminal half of hexokinase II, which is catalytically active and contains the mitochondrion-binding domain, consistently antagonized tBID-induced apoptosis. These results suggest that Akt inhibits BID-mediated apoptosis downstream of BID cleavage via promotion of mitochondrial hexokinase association and antagonism of tBIDmediated BAX and BAK activation at the mitochondria.

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Section: Discussionmentioning

confidence: 96%

Akt Inhibits Apoptosis Downstream of BID Cleavage via a Glucose-Dependent Mechanism Involving Mitochondrial Hexokinases

Majewski¹,

Nogueira²,

Robey

et al. 2004

Molecular and Cellular Biology

272

198

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“…This is in full agreement with our dynamic model that translocation contact sites can be formed wherever outer and inner membranes are in close proximity. In line with this, the frequency of contact sites observed by electron microscopic techniques seems to depend on the metabolic state of mitochondria (Hackenbrock, 1968;Van Venetie and Verkleij, 1982;Brdiczka et al, 1990). Relation to Protein Secretion in Bacteria How does mitochondrial protein import relate to protein export across two membranes in gram-negative bacteria?…”

Section: Organization Of the Import Machinery In The Mitochondrialmentioning

confidence: 95%

A dynamic model of the mitochondrial protein import machinery

Pfanner

Rassow

Klei

et al. 1992

Cell

155

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Many proteins are translocated into or across two membranes in order to reach their functional destination; these include many nuclear-encoded mitochondrial and chloroplast proteins, as well as proteins transported into or across the outer membrane of gram-negative bacteria. In eukaryotes, mechanistic insights have been obtained mainly with the mitochondrial two-membrane transport system. By generating translocation intermediates that span both mitochondrial membranes at the same time, it has been demonstrated that the outer and inner membrane translocation machineries cooperate in the import of preproteins (Hart1 and Neupert, 1990;Baker and Schatz, 1991). Translocation contact sites were defined as mitochondrial import sites where the outer and inner membranes are so close together that they can be spanned by a single polypeptide chain (Schleyer and Neupert, 1985). On the other hand, the outer and inner membranes each contain atranslocation machinery(e.g., receptors, translocation pores) that can act independently of the other (Pfanner and Neupert, 1987;Glick et al., 1991;Hwang et al., 1991;Rassow and Pfanner, 1991).The most intriguing questions concerning the mitochondrial two-membrane transport system are how the transport machineries are distributed over the two membranes and how they cooperate. This involves the problems of how the machineries of the inner and outer membranes find each other, and how the membranes are organized to allow a productive interaction. Furthermore, it is important to know how the two translocation systems are arranged to allow translocation of proteins to the inner membrane or matrix without intermittent release of the precursors into the intermembrane space. Here we consider the function and distribution of the mitochondrial translocation machinery under the conditions prevailing in the intact cell. Stimulated by several recent findings, we present a dynamic model of protein translocation across both mitochondrial membranes. This concept puts particular emphasis on the subcompartmentation of the inner mitochondrial membrane and its relation to the outer membrane. It provides also an interpretation for previous findings that could not be explained by the current static models of the mitochondrial import apparatus. MitochondrialInner and Outer Boundary Membranes The organization of the mitochondrial inner membrane is of particular importance. Two regions of the inner membrane can be distinguished in electron micrographs of mitochondria as they appear in intact cells (isotonic, orthodox conditions) (Figure 1): those parts that are in proximity to the outer membrane (the inner boundary membrane) and Minireview the remaining parts that form the cristae. Limited areas of the outer and inner boundary membranes stay in such stable contact that they are not separated by mechanical forces (such as those generated by swelling or shrinking of mitochondria) or after removal of the bulk of the outer membrane with detergent. These membrane adhesion sites, or morphological contact sites/areas, c...

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“…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). Hexokinase is activated by binding to mitochondria, and binding depends on frequency of contact sites and on metabolic state (binding increased by adrenaline and decreased by glucose or fatty acids in liver) (see Brdiczka et al, 1990;Klug et al, 1984). These findings have led to the concept of contact sites as a microcompartment where creatine kinase and hexokinase (and glycerol kinase) have preferential access to ATP exported by the adenine nucleotide carrier, and the efficiency of this microcompartment is regulated by a variety of metabolic signals.…”

mentioning

confidence: 99%

Control of respiration and ATP synthesis in mammalian mitochondria and cells

Brown

1992

Biochemical Journal

564

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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Characterization and metabolic function of mitochondrial contact sites

Cited by 33 publications

References 27 publications

Akt Inhibits Apoptosis Downstream of BID Cleavage via a Glucose-Dependent Mechanism Involving Mitochondrial Hexokinases

Akt Inhibits Apoptosis Downstream of BID Cleavage via a Glucose-Dependent Mechanism Involving Mitochondrial Hexokinases

A dynamic model of the mitochondrial protein import machinery

Control of respiration and ATP synthesis in mammalian mitochondria and cells

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