Apoptosis normally proceeds in an orderly manner as part of natural cell turnover and development, but that's not the only path to death. A quick influx of calcium ions, or extreme oxidative stress, as happens in cases of stroke, heart attack, or other ischemic events, can cause mitochondria to swell and burst, releasing necrotic mediators. The path that cells take appears intimately linked with the permeability of mitochondrial membranes.
Four groups, publishing in 2005, independently showed that the mitochondrial protein cyclophilin D (CyPD) can mediate the transition to mitochondrial permeability that leads to necrotic cell death.
Pointing to the Pore
These papers confirmed suspicions about the interaction of CyPD and the permeability transition pore that researchers had observed pharmacologically: Cyclosporin A targets cyclophilin proteins minimizing mitochondrial destruction. The groups demonstrated the connection by knocking out CyPD in mouse mitochondria and then inducing ischemia, while recording the response. In response to Ca2+ influx or oxidative stress, mitochondria lacking CyPD had limited pore opening and cell death.
Yoshihide Tsujimoto's group, at the Osaka Medical School in Japan, showed in their Hot Paper that in various cell types lacking CyPD, apoptosis still occurs, further linking the CyPD protein to necrosis.
The picture isn't yet complete. While these papers showed that mitochondria lacking the CyPD protein were protected from reperfusion, very high Ca2+ levels could still induce pore opening. Also, the Molkentin group showed that the permeability transition pore could be involved in cases of apoptosis, given high levels of CyPD.
"The pore can open even in the absence of cyclophilin D or in the presence of cyclosporin A," says Paolo Bernardi, senior author on a fourth CyPD-knock out paper.
Pointing to Drug Targets
Speculation is widespread about the structure and activity of the pore, and the role that CyPD plays in stable, healthy cells remains undefined. Nonetheless, researchers still consider CyPD a strong target for mediating cell trauma after ischemic events such as stroke or heart attack. Indeed, in the 2005 paper that Stanley Korsmeyer's lab published, cerebral ischemia was used as the model to test protection against injury by CyPD-deficient mitochondria.
Continued research has focused on both necrotic and apoptotic events, some of which can be mediated by cyclophilin inhibitors such as cyclosporin A. Alessia Angelin, in Bernardi's lab, has shown that cyclosporin A can mitigate fiber disintegration in muscular dystrophy.
Andrew Halestrap, from the University of Bristol, who was not involved in any of the studies, has worked with the Debio compound but doesn't see it having a future in protecting against ischemic trauma. "Our own work is to find better mimics of preconditioning to block the pore, rather than relying on the cyclosporin," Halestrap says. Preventing the entire chain of events that leads to mitochondrial explosion may be more practical than treating cells with necrotic mediators after ischemic injury has occurred, he adds.
C.P. Baines et al., "Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death," Nature, 434:658-62, 2005. (Cited in 120 papers) T. Nakagawa et al., "Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death," Nature, 434:652-8, 2005. (Cited in 112 papers)
Naturally, understanding cell death is vital to cancer studies as well. The two Hot Papers, and accompanying research, established a potential target for apoptosis induction in cancer therapy: Successful protection from reperfusion achieved by knocking out CyPD indicates an important role of the ANT protein. The CyPD mice experiments were also ideal in that they demonstrated natural cell function, even without the missing protein, a result that surprised other researchers such as Guido Kroemer from the Gustave Roussy Institute in France. This will help them locate the key protein targets for inducing cell death without ruining the entire function of the cell.
Mitochondria in cancer cells have shown strong resistance to calcium ions and therefore do not easily open their necrotic pores. "The challenge is to take advantage of this distinct [characteristic] and make drugs that target the cancer mitochondria and leave the regular mitochondria alone."
References
1. C.P. Baines et al., "Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death," Nature, 434:658-62, 2005. (Cited in 120 papers) 2. T. Nakagawa et al., "Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death," Nature, 434:652-8, 2005. (Cited in 113 papers) 3. E. Basso et al., "Properties of the permeability transition pore in mitochondria devoid of cyclophilin D," J Biol Chem, 280:18558-61, 2005. (cited in 57 papers) 4. A. Schinzel et al., "Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia," Proc Natl Acad Sci, 102:12005-10, 2005. (cited in 26 papers) 5. A. Angelin et al., "Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins," Proc Natl Acad Sci, 104:991-6, Jan. 16, 2007.Interested in reading more?
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