Disruption of Mitochondrial Function during Apoptosis Is Mediated by Caspase Cleavage of the p75 Subunit of Complex I of the Electron Transport Chain

Ricci, Jean-Ehrland; Muñoz-Pinedo, Cristina; Fitzgerald, Patrick; Bailly-Maître, Béatrice; Perkins, Guy; Yadava, Nagendra; Scheffler, Immo E.; Ellisman, Mark H.; Green, Douglas R.

doi:10.1016/j.cell.2004.05.008

Cited by 555 publications

(465 citation statements)

References 51 publications

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“…GA, caspase-3 and now GB proteolyzed subunits of complex I to induced ROS-dependent apoptosis, 15,16 making Figure 6 GB disrupts complex I and III activity. (a and b) Purified mouse liver mitochondria in respiration buffer were stimulated with glutamate/malate (a) or succinate (b) and O 2 consumption was measured using a Clark electrode.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of ROS has been previously demonstrated for caspase-3 and granzyme A (GA) pathways through the cleavage of NDUFS1 and NDUFS3, respectively. [15][16][17][18] GA induces cell death in a Bcl-2-insensitive and caspase-and MOMP-independent manner that has all the morphological features of apoptosis. 1,[16][17][18][19][20] As GA and GB cell death pathways are significantly different, whether ROS are also critical for GB still need to be tested.…”

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confidence: 99%

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Granzyme B-induced mitochondrial ROS are required for apoptosis

et al. 2014

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Caspases and the cytotoxic lymphocyte protease granzyme B (GB) induce reactive oxygen species (ROS) formation, loss of transmembrane potential and mitochondrial outer membrane permeabilization (MOMP). Whether ROS are required for GBmediated apoptosis and how GB induces ROS is unclear. Here, we found that GB induces cell death in an ROS-dependent manner, independently of caspases and MOMP. GB triggers ROS increase in target cell by directly attacking the mitochondria to cleave NDUFV1, NDUFS1 and NDUFS2 subunits of the NADH: ubiquinone oxidoreductase complex I inside mitochondria. This leads to mitocentric ROS production, loss of complex I and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junctions. Furthermore, we have also found that GB-induced mitocentric ROS are necessary for optimal apoptogenic factor release, rapid DNA fragmentation and lysosomal rupture. Interestingly, scavenging the ROS delays and reduces many of the features of GB-induced death. Consequently, GB-induced ROS significantly promote apoptosis. Cell Death and Differentiation (2015) 22, 862-874; doi:10.1038/cdd.2014.180; published online 31 October 2014To induce cell death, human granzyme B (GB) activates effector caspase-3 or acts directly on key caspase substrates, such as the proapoptotic BH3 only Bcl-2 family member Bid, inhibitor of caspase-activated DNase (ICAD), poly-(ADPribose) polymerase-1 (PARP-1), lamin B, nuclear mitotic apparatus protein 1 (NUMA1), catalytic subunit of the DNAdependent protein kinase (DNA-PKcs) and tubulin. [1][2][3] Consequently, caspase inhibitors have little effect on human GB-mediated cell death and DNA fragmentation. 2 GB causes reactive oxygen species (ROS) production, dissipation of the mitochondrial transmembrane potential (ΔΨm) and MOMP, which leads to the release of apoptogenic factors such as cytochrome c (Cyt c), HtrA2/Omi, endonuclease G (Endo G), Smac/Diablo and apoptosis-inducing factor, from the mitochondrial intermembrane space to the cytosol. [4][5][6][7][8][9][10][11] Interestingly, cells deficient for Bid, Bax and Bak are still sensitive to human GB-induced cell death, 5,11-13 suggesting that human GB targets the mitochondria in another way that needs to be characterized. Altogether, much attention has been focused on the importance of MOMP in the execution of GB-mediated cell death, leaving unclear whether ROS production is a bystander effect or essential to the execution of GBinduced apoptosis. The mitochondrial NADH: ubiquinone oxidoreductase complex I is a key determinant in steadystate ROS production. This 1 MDa complex, composed of 44 subunits, 14 couples the transfer of two electrons from NADH to ubiquinone with the translocation of four protons to generate the ΔΨm. The importance of ROS has been previously demonstrated for caspase-3 and granzyme A (GA) pathways through the cleavage of NDUFS1 and NDUFS3, respectively. [15][16][17][18] GA induces cell death in a Bcl-2-insensitive and caspase-and MOMP-indepen...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Granzyme B-induced mitochondrial ROS are required for apoptosis

et al. 2014

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“…The oocytes were embedded in agarose and prepared for tomography using conventional protocols for good structural preservation. 32 To survey the preservation quality of the oocytes, thinsectioned materials (B80 nm) were examined using a JEOL 1200FX electron microscope. Three-dimensional reconstructions of portions of the cell containing mitochondria were generated using standard techniques.…”

Section: Discussionmentioning

confidence: 99%

Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure

et al. 2006

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Although the identification of specific genes that regulate apoptosis has been a topic of intense study, little is known of the role that background genetic variance plays in modulating cell death. Using germ cells from inbred mouse strains, we found that apoptosis in mature (metaphase II) oocytes is affected by genetic background through at least two different mechanisms. The first, manifested in AKR/J mice, results in genomic instability. This is reflected by numerous DNA double-strand breaks in freshly isolated oocytes, causing a high apoptosis susceptibility and impaired embryonic development following fertilization. Microinjection of Rad51 reduces DNA damage, suppresses apoptosis and improves embryonic development. The second, manifested in FVB mice, results in dramatic dimorphisms in mitochondrial ultrastructure. This is correlated with cytochrome c release and a high apoptosis susceptibility, the latter of which is suppressed by pyruvate treatment, Smac/DIABLO deficiency, or microinjection of 'normal' mitochondria. Therefore, background genetic variance can profoundly affect apoptosis in female germ cells by disrupting both genomic DNA and mitochondrial integrity.

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“…mPT has also been implicated in necrosis [7,96]. Caspase 3 activation resulting from cytochrome c release can stimulate mPT [69,111], which can subsequently act as a feed-forward mechanism for further cytochrome c release.…”

Section: Apoptosismentioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

219

183

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SummaryRho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and animal disease models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, based largely on kinase construct overexpression, and chemical inhibitors (Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights the new findings from recently generated ROCK-deficient mice.

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Disruption of Mitochondrial Function during Apoptosis Is Mediated by Caspase Cleavage of the p75 Subunit of Complex I of the Electron Transport Chain

Cited by 555 publications

References 51 publications

Granzyme B-induced mitochondrial ROS are required for apoptosis

Granzyme B-induced mitochondrial ROS are required for apoptosis

Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure

Rho kinase in the regulation of cell death and survival

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