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Inhibition of Mitochondrial Respiratory Chain Complex I by TNF Results in Cytochrome C Release, Membrane Permeability Transition, and Apoptosis{

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Inhibition of Mitochondrial Respiratory Chain Complex I by TNF Results in Cytochrome C Release, Membrane Permeability Transition, and Apoptosis{ Oncogene (1998) 17, 2515 ± 2524 ã 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Inhibition of mitochondrial respiratory chain complex I by TNF results in cytochrome c release, membrane permeability transition, and apoptosis{ Masahiro Higuchi*,1, Rita J Proske1 and Edward TH Yeh1,2 1Research Center for Cardiovascular Diseases, Institute of Molecular Medicine for the Prevention of Human Diseases and 2Division of Molecular Medicine, The University of Texas-Houston Health Science Center, Houston, Texas 77030, USA Mitochondria have been shown to play a key role in apoptosis-inducing protein apoptogeneic protease apoptosis induction. However, the sequence of changes (Susin et al., 1996) is released from mitochondria. that occur in the mitochondria in the initial step of Several reagents can open mitochondrial permeability apoptosis has not been clearly elucidated. Here, we transition pores, leading to a release of apoptogeneic showed that mitochondrial respiratory chain (MRC) protease and caspase 3 activation (Susin et al., 1997). complex I was inhibited during the early phase of Inducers of MPT can release cytochrome c from TNF- or serum withdrawal apoptosis. The importance mitochondria (Yang and Cortopassi, 1998). However, of complex I inhibition in apoptosis is also supported by the induction of MPT is not always necessary for the the observation that rotenone, an inhibitor of complex I release of cytochrome c (Yang et al., 1997). Several but not that of other complexes, could induce apoptosis reports have shown that reactive oxygen species (ROS), in a manner comparable to TNF. We hypothesized that phospholipases, and Ca2+ ions can promote the inhibition of complex I could aect electron ¯ow through induction of MPT (Skulachev, 1996); however, the other complexes leading to cytochrome c release by an link between the stimulus of MPT inducing reagents antioxidant-sensitive pathway and caspase 3 activation and the induction of MPT is not clear. Overexpression followed by the induction of membrane permeability of bcl-2 abrogated TNF-induced apoptosis, increased transition (MPT). This hypothesis is supported by the mitochondrial membrane potential (Marchetti et al., following observations: (1) TNF and rotenone induced 1996), and inhibited cytochrome c release (Kluck et al., MPT and cytochrome c release; (2) TNF-induced 1997; Yang et al., 1997). This suggests that these events complex I inhibition was observed prior to cytochrome c are closely related during apoptosis. However, the release and MPT induction; (3) MPT induction was relationship between MPT induction and cytochrome c inhibited by a caspase 3 inhibitor, z-DEVD-CH2F, and release in TNF-induced apoptosis has not yet been an antioxidant pyrrolidine dithiocarbamate (PDTC), elucidated. whereas cytochrome c release was only inhibited by Involvement of mitochondria has been implicated in PDTC. Thus, these results suggest that MRC complex I TNF-induced cell death. During the early stage of cell plays a key role in apoptosis signalings. death induced by TNF, mitochondria swell (Rutka et al., 1988) and mitochondrial respiration chains (MRC) Keywords: reactive oxygen species; caspases; apoptosis; are inhibited (Higuchi et al., 1992; Schulze-Ostho et necrosis; cytochrome al., 1992). Because mitochondria are the source of ATP, inhibition of MRC will ultimately decrease cellular ATP levels leading to cell death. Additional mechanisms may be involved in TNF-induced cyto- Introduction toxicity. Since mitochondria are the main source of ROS, which have been implicated in both apoptosis Changes in mitochondrial function are thought to be and necrosis (Lennon et al., 1991), mitochondria- involved in apoptois induction. In staurosporine- derived ROS may provide a link between mitochon- induced apoptosis, cytochrome c is released from dria and cell death. This hypothesis is also supported mitochondria which leads to the activation of by the observation that under low oxygen conditions, caspase 3 (Li et al., 1997; Liu et al., 1996). It is very TNF-induced cytotoxicity was reduced (Matthews et likely that cytochrome c release from mitochondria can al., 1987). Furthermore, manganese superoxide dis- induce apoptosis, however several other reports imply mutase (Mn SOD), located in mitochondria, dismu- dierent roles of cytochrome c in apoptosis signaling tates mitochondrial superoxide anion, which has leaked (Adachi et al., 1997; Tang et al., 1998). In from the electron transport chain, and abrogates TNF- dexamethasone-induced apoptosis, MPT is induced mediated apoptosis (Wong et al., 1989; Wong and (Macho et al., 1995; Zamzami et al., 1995) and the Goeddel, 1988). In contrast, Zn/Cu SOD, which is located in the cytosol, does not inhibit TNF-induced apoptosis. Furthermore, TNF increased hydrogen peroxide generation in the mitochondria in certain *Correspondence: M Higuchi, Institute of Molecular Medicine for systems (Hennet et al., 1993) and inhibited MRC the Prevention of Human Diseases, 2121 W. Holcombe, Houston, through antioxidant-sensitive pathway (Higuchi et al., TX 77030, USA 1992). These results indicate that superoxide anion {This is publication number 135-IMM from the institute of from MRC is involved in TNF-induced cell death. Molecular Medicine for the Prevention of Human Diseases, It is likely that respiratory function may aect University of Texas-Houston Health Science Center Received 28 July 1998; revised 2 October 1998; accepted 9 October oxidative stress. In a previous study to investigate the 1998 requirements of mitochondrial respiratory function in Mitochondrial respiration chains and apoptosis MHiguchiet al 2516 TNF-induced apoptosis signaling, we generated a panel Results of respiration de®cient clones and their reconstituted cybrids with normal mitochondria (Higuchi et al., Inhibition of MRC complex I by TNF and serum 1997). We showed that mitochondrial respiratory starvation activity correlated with the ability of TNF, anti-Fas antibody, and serum starvation, but not staurosporine, We have shown previously that mitochondrial respira- to induce apoptosis. Our study placed mitochondrial tory function is involved in the induction of apoptosis respiratory function at a step prior to the activation of by TNF, anti-Fas, and serum starvation (Higuchi et a caspase 3-like protease in TNF-induced apoptosis al., 1997). Inhibition of certain components of MRC signaling. Therefore, it is very likely that TNF aects can aect electron ¯ow and regulate apoptotic mitochrondrial respiratory function and then activates response. Figure 1 shows the MRC complexes caspase 3 through a respiratory function dependent involved in the mitochondrial electron transfer fashion. However, changes in mitochondrial respira- system. Initially, we investigated the eect of TNF on tory function by TNF-induced apoptosis have not been MRC complexes in ML-1a cells. A 90 min treatment of elucidated. ML-1a cells with TNF plus protein synthesis inhibitor Mitochondrial respiratory chain is composed of ®ve cycloheximide induced apoptosis (Higuchi et al., 1995). enzyme complexes: NADH:ubiquinone oxidoreductase Cells were treated with TNF and cycloheximide for the (complex I), succinate:ubiquinone oxidoreductase times indicated in Figure 2 and then tested for their (complex II), ubiquinone:ferricytochrome c oxidore- eect on MRC activity. A 10 min treatment of ML-1a ductase (complex III), ferrocytochrome c: oxygen cells with TNF abrogated 25% of the malate/ oxidoreductase (complex IV), and F0F1-ATPase glutamate-dependent oxygen consumption, which (complex V). As shown in Figure 1, complexes I, II, measures electron ¯ow through complexes I, III and III and IV plus coenzyme Q and cytochrome c make IV (see Figure 1), whereas the same treatment showed up MRC and complex V generates ATP by coupling no eect on succinate-dependent oxygen consumption, with the proton energy generated at complex I, III and which measures electron ¯ow through complexes II, III IV. Several reports imply that the damage to complex- and IV (Figure 2). A 20 min treatment inhibited 84% es I and III can induce apoptosis (Guidarelli et al., of malate/glutamate-dependent oxygen consumption 1996; Hartley et al., 1994) and that complex V might and 41% of succinate-dependent consumption (Figure be involved in apoptosis (Matsuyama et al., 1998). 2). These results indicate that MRC complex I was In this paper, we investigated the role of MRC inhibited prior to the inhibition of complexes II, III during an early step of apoptotic signaling. We and IV. demonstrated that the inhibition of MRC complex I We also investigated whether the speci®c inhibition occurs during the early stages of mitochondrial changes of MRC complex I could be observed in apoptosis in apoptosis. We also showed that inhibition of MRC complex I released cytochrome c from mitochondria and induced MPT. Furthermore, we investigated the involvement of an antioxidant-sensitive pathway and caspases in cytochrome c release and MPT induction by complex I inhibition leading to apoptosis. Figure 2 Kinetics of TNF-induced inhibition of the respiration 7 Figure 1 Electron ¯ow through mitochondrial respiratory chain chains. 3610 ML-1a cells were incubated with 1 nM TNF for the complexes. Malate/glutamate, succinate a-glycerophosphate, and indicated times and then the rates of O2 uptake was measured as ascorbate/TMPD are substrates. CoQ: coenzyme Q, cyt. C: described under Materials and methods. The concentrations of cytochrome C substrates were 5
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