Bax regulates primary necrosis through mitochondrial dynamics

Abstract

The defining event in apoptosis is mitochondrial outer membrane permeabilization (MOMP), allowing apoptogen release. In contrast, the triggering event in primary necrosis is early opening of the inner membrane mitochondrial permeability transition pore (mPTP), precipitating mitochondrial dysfunction and cessation of ATP synthesis. Bcl-2 proteins Bax and Bak are the principal activators of MOMP and apoptosis. Unexpectedly, we find that deletion of Bax and Bak dramatically reduces necrotic injury during myocardial infarction in vivo. Triple knockout mice lacking Bax/Bak and cyclophilin D, a key regulator of necrosis, fail to show further reduction in infarct size over those deficient in Bax/Bak. Absence of Bax/Bak renders cells resistant to mPTP opening and necrosis, effects confirmed in isolated mitochondria. Reconstitution of these cells or mitochondria with wild-type Bax, or an oligomerization-deficient mutant that cannot support MOMP and apoptosis, restores mPTP opening and necrosis, implicating distinct mechanisms for Bax-regulated necrosis and apoptosis. Both forms of Bax restore mitochondrial fusion in Bax/Bak-null cells, which otherwise exhibit fragmented mitochondria. Cells lacking mitofusin 2 (Mfn2), which exhibit similar fusion defects, are protected to the same extent as Bax/Bak-null cells. Conversely, restoration of fused mitochondria through inhibition of fission potentiates mPTP opening in the absence of Bax/Bak or Mfn2, indicating that the fused state itself is critical. These data demonstrate that Bax-driven fusion lowers the threshold for mPTP opening and necrosis. Thus, Bax and Bak play wider roles in cell death than previously appreciated and may be optimal therapeutic targets for diseases that involve both forms of cell death.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…Recent genetic studies revealed that deletion of Bax/ Bak inhibits mPTP opening and necrotic cell death induced by Ca 2+ overload or ROS, suggesting the ability of Bax/Bak to facilitate mPTP-induced cell death. 113,114 Thus the aforementioned mitoHK-II-mediated inhibition of Bax binding to mitochondria could contribute to the anti-mPTP effect of mitoHK-II. Further studies will be required to delineate the interaction of these molecules to determine the mechanism by which HK-II prevents mPTP opening.…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…Although MOMP and mPTP appear to be distinct pathways, a cross-talk has been reported between them. Mice deficient in Bax/Bak render cells resistant to mPTP opening and necrosis (451). Superoxide-induced mitochondrial Cyt-c release in HepG2 cells depends on VDAC, and blockers of VDAC inhibited the release (259).…”

Catch me if you can: targeting the mitochondrial permeability transition pore in myocardial infarction

“…This may be significant with respect to the variability in cardioprotection provided by cyclosporine A because the fused mitochondrial state sensitizes to mPTP opening. 14 Second, although experiments using mice lacking cyclophilin D 8,9 and cyclosporine A 3 implicate mPTP opening in reperfusion injury, might other death processes provide redundancy when mPTP opening is inhibited? In fact, genetic and pharmacological data suggest that necroptosis may contribute to infarct size in heart and kidney following ischemia/reperfusion injury.…”