Cited by 291Cell death mechanisms and regulationMitochondrial Function and PathologyCardiac Ischemia and Reperfusion

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Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice

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Karch, Jason, Kwong, Jennifer Q, Burr, Adam R, Sargent, Michelle A, Elrod, John W, Peixoto, Pablo M, Martinez-Caballero, Sonia, Osinska, Hanna, Cheng, Emily H-Y, Robbins, Jeffrey, Kinnally, Kathleen W, Molkentin, Jeffery D·2013·eLife

DOI 10.7554/elife.00772PMC PMC3755340

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Abstract

A critical event in ischemia-based cell death is the opening of the mitochondrial permeability transition pore (MPTP). However, the molecular identity of the components of the MPTP remains unknown. Here, we determined that the Bcl-2 family members Bax and Bak, which are central regulators of apoptotic cell death, are also required for mitochondrial pore-dependent necrotic cell death by facilitating outer membrane permeability of the MPTP. Loss of Bax/Bak reduced outer mitochondrial membrane permeability and conductance without altering inner membrane MPTP function, resulting in resistance to mitochondrial calcium overload and necrotic cell death. Reconstitution with mutants of Bax that cannot oligomerize and form apoptotic pores, but still enhance outer membrane permeability, permitted MPTP-dependent mitochondrial swelling and restored necrotic cell death. Our data predict that the MPTP is an inner membrane regulated process, although in the absence of Bax/Bak the outer membrane resists swelling and prevents organelle rupture to prevent cell death.

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Figure 1. Bax/Bak1 DKO MEFs are resistant to a necrotic-like cell death. (A)–(C) MultiTox-Fluor multiplex cytotoxicity assay, which measures membrane (mem) integrity loss induced death, for different time points in cultures of Wt and Bax/Bak1 DKO MEFs treated with staurosporine (St), H2O2, ionomycin (Iono) for different time points. (D) Propidium iodide (PI) inclusion to assess membrane integrity following methyl methanesulfonate (MMS) for different time points. (E) Transmission electron microscopy of Wt and DKO MEFs treated with the indicated agents for 10 hr (St, 200 nM) or 20 hr (Iono, 20 μM). Magnification is ×10,000 for all panels. (F) and (G) FACS quantitation of annexin V and PI staining of DKO MEFs treated with H2O2 (800 μM) or ionomycin (20 μM) for the indicated time points. Apoptotic and necrotic killing was almost nonexistent in DKO MEFs compared with Wt MEFs shown in Figure 1—figure supplement 1. (H) PI inclusion rates for cell death assessment in DKO MEFs or DKO MEFs expressing a stable cDNA for Bax or Bak with the indicated death inducing agents for 20 hr. #p<0.05 vs DKO alone. (I) PI inclusion rates for cell death assessment in DKO MEFs and DKO MEFs infected with a Bax expression adenovirus following stimulation with the indicated death-inducing agents for 12 (St) or 24 hr (H2O2, Iono). #p<0.05 vs DKO alone. (J) and (K) Oxygen consumption rates (OCR) in cultures of Wt (J) or DKO (K) MEFs treated with St (200 nM) or Iono (20 μM) for the indicated time points. Rates are expressed as pmol/min per 1000 cells in a well of a 24-well dish. All assays were performed in duplicate and averaged from three independent experiments. *p<0.05 vs 0 time point; #p<0.05 vs no treatment. DOI: http://dx.doi.org/10.7554/eLife.00772.003CC BY · PubMed Central

Figure 1—figure supplement 1. Conditions whereby staurosporine induces only apoptosis while ionomycin induces necrosis in cultured Wt MEFs. (A). Immunocytochemistry for propidium iodide (PI, red), annexin V (green), or a merged channel with Hoechst (blue for nuclei) in Wt MEFs treated with staurosporine (St) for 6 hr, H2O2 for 12 hr, or ionomycin (Iono) for 20 hr (B)–(D) FACS analysis of Wt MEFs treated with St (200 nM), H2O2 (800 μM), or Iono (20 μM) for the indicated times, after which cultures were lifted from the plates and sorted for annexin V (AnxV) or annexin V with PI. Annexin V only cells are apoptotic, whereas annexin V with PI labeled cells are necrotic. *p<0.05 vs PI + AnxV in (B) or vs AnxV in (D). Results were averaged from three independent experiments. (E) Western blot quantitation for cleaved caspase 3 from Wt MEFs treated with the agents shown under conditions shown in (A). Cleaved caspase 3 is a reflection of apoptosis induction, which is highly correlated with St (200 nM, 8 hr) treatment but not Iono (20 μM, 12 hr) or H2O2 (800 μM, 12 hr). (F) Cell death assay for PI positivity in Wt MEFs in the presence of the indicated pro-death agents for the times shown in (A) with or without caspase inhibition with z-Vad. Caspase inhibition only reduced apoptotic death induced by St. *p<0.05 vs none (n = 3 experiments). St (200 nM, 12 hr), Iono (20 μM, 16 hr), and H2O2 (800 μM, 12 hr). (G) Cell death assay for PI positivity in Wt and Ppif null MEFs with the indicated pro-death agents. Ppif null MEFs reduced cell death with H2O2 or ionomycin necrotic stimulation but not with the apoptotic stimuli staurosporine (St). *p<0.0001 vs Wt control, n = 3 independent experiments. St (200 nM, 24 hr), Iono (20 μM, 24 hr), H2O2 (800 μM, 24 hr). (H) Western blot showing cyclophilin D and GAPDH (control) protein levels from Wt and Ppif knockout MEFs. DOI: http://dx.doi.org/10.7554/eLife.00772.004CC BY · PubMed Central

Figure 1—figure supplement 2. Bax/Bax1 null MEFs (DKO) have normal mitochondrial protein content except for a slight upregulation of Bim and BNip3. Western blotting of protein extracts fractionated as cytosol or purified mitochondria for the indicated proteins. Metabolic proteins were unchanged in Bax/Bak1 null MEFs vs Wt MEFs, as were cyclophilin D (CypD) and VDAC1. Other Bcl-2 family members were unchanged apart from a slight increase in Bim and Bnip3. Bax and Bak protein was missing. β-tubulin shows successful fractionation of just the cytosol. DOI: http://dx.doi.org/10.7554/eLife.00772.005CC BY · PubMed Central

Figure 1—figure supplement 3. Bax/Bak1-deficient mitochondria remain coupled for ATP generation after ionomycin treatment. (A) and (B) Oxygen consumption rates (OCR) in 24-well dish cultures of Wt (A) or DKO (B) MEFs treated with St (200 nM) or Iono (20 μM) for 12 hr and then sequentially treated with 2 μM oligomycin (oligo), 3 μM FCCP or 4 μM Antimycin A (ANT A). Rates are expressed as pmoles/min per 1000 cells. All assays were performed in duplicate and averaged from three independent experiments. DOI: http://dx.doi.org/10.7554/eLife.00772.006CC BY · PubMed Central

Figure 2. Bax/Bak-deficient mitochondria are resistant to swelling and MPTP formation. (A)–(D) Mitochondrial absorbance change swelling assay upon Ca2+ (A and B) or atractyloside (Atr. C and D) addition (arrowhead) in mitochondria purified from Wt or DKO MEFs. CsA (2 μM) is given to desensitize MPTP-induced swelling as a control. (E)–(G) Swelling assays in mitochondria purified from mouse hearts of the indicated genotypes. Ca2+ is added at a given time (arrowhead), and CsA (2 μM) is a control that desensitizes MPTP formation and swelling. (H)–(J) Swelling assays in mitochondria purified from mouse livers of the indicated genotypes. Ca2+ is added at a given time (arrowhead), and CsA (2 μM) is a control that desensitizes MPTP formation and swelling. (K) and (L) Ca2+ uptake capacity assay with the external Ca2+ indicator dye calcium green-5N with purified mitochondria from Wt or DKO MEFs. 50 (K) or 100 μM (L) cumulative Ca2+ additions are shown at each arrowhead. Fluorescence diminishes as the mitochondria remove the Ca2+ from the solution until the MPTP opens and Ca2+ is no longer sequestered. CsA is given to Wt mitochondria as a control to show the closed state of the MPTP. The swelling and Ca2+ uptake assays were performed in three independent experiments, although representative tracings are shown. DOI: http://dx.doi.org/10.7554/eLife.00772.007CC BY · PubMed Central

Figure 2—figure supplement 1. Cardiac-specific Bax/Bak1 deficiency renders the heart partially resistant to cell death after ischemic reperfusion (I-R) injury. (A) Western blotting for Bak and Bax protein from the heart of Wt mice containing the αMHC-Cre transgene, Bak1−/− only mice, and Bak1−/− mice with two Bax-loxP targeted alleles with the αMHC-Cre transgene, the later of which deletes greater than 90% of all Bax protein only in cardiac myocytes. (B) Survival of mice after myocardial infarction (MI) injury in which the left coronary artery was permanently ligated. Sham mice of all genotypes showed no lethality, but the WtαMHC-Cre control mice showed 80% lethality after MI, which was significantly reduced in mice lacking Bax/Bak protein in the heart, showing protection from MI-related death of the mice. (C) Histological analysis of mouse hearts from the indicated genotypes after ischemia for 1 hr and reperfusion for 24 hr stained with 2,3,5-triphenyltetrazolium chloride (TTC) to show area of infarction (white area did not stain and is dead tissue), which was much larger in Wt controls (WtαMHC-Cre) than in Bax/Bak1-deleted mice (the hashed area outlines the area of injury in the heart). (D) Quantitation of the data shown in (C). #p<0.05 vs Wt control mice; n = >8 mice in each group. IA/AAR = ischemic area/area at risk. DOI: http://dx.doi.org/10.7554/eLife.00772.008CC BY · PubMed Central

Figure 2—figure supplement 2. Liver-specific Bax/Bak1 deletion with the albumin-Cre transgene. The Cre allele deletes approximately 90% of all protein from the liver as shown by Western blotting for Bak and Bax protein from the liver of Wt mice (WtAlb-Cre), Bak1−/− only, or Bak1−/− mice with two Bax-loxP targeted alleles with the Alb-Cre transgene. GAPDH is a control for protein loading. DOI: http://dx.doi.org/10.7554/eLife.00772.009CC BY · PubMed Central

Figure 2—figure supplement 3. Atomic absorption mass spectrometry from purified mitochondria from Wt or Bak1−/− BaxAlb-Cre livers. Mitochondria were treated with Ca2+ for 5 min or Ca2+ with cyclosporine A (CsA, 2 μM). The data show that mitochondria from DKO MEF mitochondria hold more Ca2+ at baseline (compare black and gray bars) and after Ca2+ challenge compared with Wt mitochondrial (compare red and orange bars). CsA did not increase the amount of Ca2+ that DKO mitochondria could absorb, but it did increase Ca2+ uptake in Wt mitochondria, suggesting that loss of Bax/Bak functions in concert with the MPTP. DOI: http://dx.doi.org/10.7554/eLife.00772.010CC BY · PubMed Central

Figure 2—figure supplement 4. Bax/Bak-deficient mitochondria are resistant to Ca2+-induced swelling but are otherwise capable of nonspecific swelling. (A)–(H) Mitochondrial absorbance change as assessment of swelling with addition of Ca2+ and 40 μM alamethicin (A, B, E, and F) or the indicated concentrations of KCl (C, D, G, and H) to affect baseline swollen state. Mitochondria were purified from Wt or DKO MEFs (A–D) or livers (E–H). (A and E) are representative traces graphed using raw absorbance values and no normalization, while (B and F) are the corresponding traces graphed as relative absorbance to normalize the baselines. The swelling assays were performed in three independent experiments, although representative tracings are shown. The data show that normalization does not affect interpretation of results and that KCl concentration differences have a similar effect on baseline swelling of Wt and DKO mitochondria from both MEFs and livers. The data also show that while mitochondria from DKO MEFs and livers remain resistant to calcium-induced swelling, the non-specific permeabilizing agent alamethicin can still cause swelling. DOI: http://dx.doi.org/10.7554/eLife.00772.011CC BY · PubMed Central

Figure 3. Nonoligomerized Bax/Bak mediate mitochondrial swelling and necrosis. (A) Quantitation by FACS analysis of Wt MEFs treated previously with the indicated stimuli. Sorting was with the activated Bax epitope mAB 6A7. The results were averaged from three independent experiments. (B) Western blotting for activated Bak from fixed cells (DSS crosslinker) that were previously stimulated with staurosporine (200 nM for 10 hr) or ionomycin (20 μM for 20 hr). (C) Western blotting for Bax after gel filtration chromatography to show increasing molecular weights of complexes in cells stimulated previously with staurosporine (200 nM for 10 hr) or ionomycin (20 μM for 20 hr). One of three independent experiments is shown, all with similar results. (D) PI incorporation cell death assay in DKO MEFs at baseline (control), DKO MEFs reconstituted with Wt Bax, or DKO MEFs reconstituted with Bax mutants (amino acids 63–65 or 92–94 were mutated to alanines) that cannot oligomerize and generate apoptotic pores in the outer mitochondrial membrane. MEFs were stimulated with staurosporine (200 nM for 24 hr) or ionomycin (20 μM for 24 hr). The results were averaged from three independent experiments. (E) Fluorescence reading of Ca2+ measured with calcium green-5N indicator in solution in the presence of purified mitochondria from the indicated MEFs. Cumulative Ca2+ additions are shown at each arrowhead. The assay was performed in three independent experiments, although representative tracings are shown. *p<0.05 vs none. DOI: http://dx.doi.org/10.7554/eLife.00772.012CC BY · PubMed Central

Figure 4. Bax/Bak-deficient mitochondria are defective in outer membrane permeability and associated swelling. (A) Transmission electron microscopy (EM) of purified Wt and Bax/Bak1-deficient (DKO) liver mitochondria at baseline (none) or with Ca2+ with or without CsA (2 μM) for 5 min prior to fixation. The arrows show swollen and rupturing mitochondria. Magnification is ×40,000 for all panels. (B) Quantitation of mitochondrial cross-sectional area in different quartiles from the type of EM data shown in (A). (C) Absorbance reading for swelling in liver-derived DKO mitochondria treated with the indicated conditions. The gray lines are the controls that represent all five Ca2+ stimulated conditions with CsA, or DKO mitochondria not stimulated with Ca2+. (D) Quantitation of the change in absorbance tracings shown in (C) for mitochondrial swelling under the indicated conditions. Four independent swelling experiments were tabulated. *p<0.05 vs DKO + Ca2+ only. (E) Absorbance reading for swelling in liver-derived Wt mitochondria treated with Ca2+ and increasing concentration of poloxamer 188 (P-188). (F) EM of purified Wt liver mitochondria with and without Ca2+, with and without 5% P-188. The arrows show swollen and rupturing mitochondria. Magnification is ×40,000 for all panels. DOI: http://dx.doi.org/10.7554/eLife.00772.013CC BY · PubMed Central

Figure 4—figure supplement 1. Bax/Bak1 DKO MEF are fully susceptible to inner membrane permeability, but resist full MPTP with Ca2+ overload. (A) Calcein–CoCl2 staining of Wt and Bax/Bak1 DKO MEFs treated with 200 nM Staurosporine (St) or 20 μM ionomycin (iono) for 15 min. Both are equally susceptible to inner membrane opening under living conditions. (B) Western blots from purified cytoplasm (without mitochondria) showing cytochrome c release and cleaved caspase 3 from Wt and DKO MEFs that were treated with 200 nM St, 800 μM H2O2, or 20 μM Iono for 6 hr. DKO MEFs do not form pores to release cytochrome c with staurosporine or rupture after H2O2 or ionomycin treatment to release cytochrome c. (C) Relative oxygen consumption rates from mitochondria isolated from Wt or DKO MEFs that were subjected to four sequential additions of 200 μM Ca2+. There was a 5-min incubation time after each injection of Ca2+. DKO mitochondria, despite transient inner membrane opening, are able to maintain respiration, likely because the lack of outer membrane permeability keeps the mitochondria intact so the inner membrane can reestablish electron transport. DOI: http://dx.doi.org/10.7554/eLife.00772.014CC BY · PubMed Central

Figure 5. Bax/Bak regulate outer mitochondrial membrane permeability directly. (A) and (B) Patch clamp current traces (2 s, 5 KHz sampling, 1 KHz filter in 0.15 M KCl media) from Wt and DKO whole mitochondria and liposomes are shown after excised patches were voltage clamped at −20 to 40 mV and reveal small variable-sized transitions, typically approximately 50–100 pS. Recombinant Bax (rBax at 50–100 ng/µl) was included in the patch pipette as indicated. Current trace recorded from a liposome with a patch pipette backfilled with media containing 10 nM rBax + 10 nM tBid reveals up to 3000 pS transitions, which are not seen with rBax alone. (C) Graph of multiple independent patch recordings of the representative traces shown in (A and B). Large channel activities, such as from TOM, were excluded from the Wt and DKO mitochondrial data set. *p<0.05 vs Wt mitochondria; #p<0.05 vs untreated liposomes. (D) Patch clamp current traces from mitoplasts (inner membrane) were recorded as in (A) from Wt and DKO mitochondria at −60 and −20 mV, respectively. (E) Graphs showing comparisons of MPTP single-channel characteristics recorded from the indicated number of independent patches of mitoplasts isolated from Wt and DKO cells. MPTP was scored present from mitoplast recordings if the peak conductance was ≥1 nS, transition sizes ≥0.3 nS, voltage dependence, and when possible, cation selectivity. (F) Western blot for the outer and inner mitochondrial membrane proteins Sam-50 and complex V/III, respectively. Samples were normalized for complex V/III to show differences in Sam-50 and proper enrichment of inner membrane in the mitoplast preparation vs whole mitochondria. (G) Absorbance reading for swelling in liver-derived Wt and DKO mitoplasts (outer membranes removed) treated with the indicated conditions. DOI: http://dx.doi.org/10.7554/eLife.00772.015CC BY · PubMed Central

Figure 6. Assessment of Ca2+ dynamics in Bax/Bak1-deficient MEFs. (A) Measurement of total cellular Ca2+ in Wt and DKO MEFs using the ratiometric Ca2+ indicator Fura-2 (read as ratio difference F340/F380). The arrowhead shows where thapsigargin, FCCP, EDTA, and ionomycin are added to release all intracellular Ca2+ from the ER and mitochondria. Two hundred Wt and 320 DKO cells were analyzed. (B) and (C) Same measurements as in (A), except that the SERCA1 inhibitor thapsigargin (B) or ATP (C) are used to release ER Ca2+ over time. The Ca2+ signal from DKO MEFs is not significantly different from Wt MEFs. Individual cells were measured on the dish while still alive. One hundred and eighty-five Wt and 282 DKO cells were analyzed for Tg, and 88 Wt and 181 DKO were analyzed for ATP. (D) Same measurements as in (A) except that only the mitochondrial Ca2+ liberating agent FCCP is given. DKO MEFs on a culture dish have greater Ca2+ release from their mitochondria than do Wt MEFs (p<0.05), suggesting greater content in the mitochondria at rest. Twenty-six Wt and 44 DKO cells were analyzed. (E) Assessment of SERCA1 overexpression in Bax/Bak1 DKO MEFs and cell death (PI positive). The data show that SERCA1 overexpression in Wt or DKO MEFs does not sensitize to cell death with ionomycin or staurosporine (N = 3 independent experiments). DOI: http://dx.doi.org/10.7554/eLife.00772.016CC BY · PubMed Central

Figure 7. Protective Bcl-2 family members are not responsible for the protection observed with Bax/Bak1 DKO and gossypol restores Ca2+-induced killing in DKO cells. (A) PI incorporation cell death assay in Wt and DKO MEFs without treatment (none) or with staurosporine (St) or ionomycin (Iono) with or without the Bcl-2/Bcl-xl inhibitor ABT-737 and or gossypol. St was used at 200 nM for 12 hr, ionomycin was used at 20 μM for 24 hr, ABT-737 was used at 20 μM, and gossypol was used at 10 μM. The results were averaged from three independent experiments. *p<0.05 vs untreated; #p<0.05 vs no ABT-737 or gossypol in St or Iono treated Wt MEFs; †p<0.05 vs ionomycin-treated DKO MEFs. (B) Ca2+ uptake capacity assay with the external Ca2+ indicator dye calcium green-5N and purified mitochondria from Wt or DKO MEFs. 75 μM Ca2+ additions are shown at each arrowhead. Fluorescence in the supernatant diminishes as the mitochondria remove the Ca2+ from the solution, until the MPTP opens and the Ca2+ is no longer sequestered. The swelling and Ca2+ uptake assays were performed over three independent experiments, although representative tracings are shown. Gossypol was given as a control for an agent that can increase the permeability of the outer mitochondrial membrane in the absence of Bax/Bak. (C) Assay similar to that shown in (B) for Ca2+ release and MPTP activity under the indicated conditions in purified Wt or DKO mitochondria. The assay was recorded continuously while 50 μM Ca2+ was given in two spikes over time, followed by treatment with ABT-737 or gossypol (given at the arrowheads). DOI: http://dx.doi.org/10.7554/eLife.00772.017CC BY · PubMed Central

Figure 8. Schematic representation of how Bax and Bak influence MPTP-dependent mitochondrial swelling and organelle rupture. The model shows mitochondria undergoing MPTP opening (blue) via CypD (yellow) in the presence and absence of Bax/Bak (red). When Bax/Bak are present on the outer membrane and the MPTP opens in response to Ca2+, it causes the mitochondrial inner membrane to dissipate its electrochemical gradient leading to additional swelling and eventually rupture of the outer membrane and entire organelle. When Bax/Bak are absent, the outer membrane has lower permeability, which prevents swelling and rupture and subsequent necrosis even though the inner membrane has undergone MPTP opening. DOI: http://dx.doi.org/10.7554/eLife.00772.018CC BY · PubMed Central

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Cell Death
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Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death
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Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
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“RIP1 is able to interact with RIP3 in controlling necroptosis (Cho et al., 2009; He et al., 2009; Zhang et al., 2009).”
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Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC
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“Over a decade ago, several reports suggested that Bax and/or Bak directly interacted with presumed components of the MPTP, the adenine nucleotide translocator (ANT) in the inner membrane and the VDAC in the outer membrane (Marzo et al., 1998; Narita et al., 1998; Shimizu et al., 1999).”
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Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions
Bernardi, P., Gerle, C., Halestrap, A. P., Jonas, E. A., Karch, J. M., Mnatsakanyan, N., Pavlov, E. V., Sheu, S., & Soukas, A. A. (2023) · Cell Death and Differentiation · doi:10.1038/s41418-023-01187-0 · Cited by 504
“It has been proposed that such a “supercomplex” could be present preferentially at contact sites between the outer and inner membrane [23, 120, 121].”
BackgroundSelf-citation
Physiological and Pathological Roles of the Mitochondrial Permeability Transition Pore in the Heart
Kwong, J. Q., & Molkentin, J. D. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.001 · Cited by 472
“…inhibition of MPTP opening by deletion of MPTP components, notably the genes encoding CypD (Baines et al., 2005; Nakayama et al., 2007), PiC (Kwong et al., 2014), and Bax/ Bak (Karch et al., 2013; Whelan et al., 2012), reduced cardiac damage sustained in response to ischemia-reperfusion injury.”
BackgroundInfluentialSelf-citation
The mitochondrial permeability transition: A current perspective on its identity and role in ischaemia/reperfusion injury
Halestrap, A. P., & Richardson, A. P. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.08.018 · Cited by 477
Mitochondrial Function, Biology, and Role in Disease
Murphy, E., Ardehali, H., Balaban, R. S., Lisa, F. D., Dorn, G. W., Kitsis, R. N., Otsu, K., Ping, P., Rizzuto, R., Sack, M. N., et al. (2016) · Circulation Research · doi:10.1161/res.0000000000000104 · Cited by 476
“Recently, the proapoptotic proteins BAX and BAK were found to be critical mediators of primary necrosis.(163,186) Mice lacking BAX and BAK or BAX alone exhibit markedly decreased cardiac necrosis, apoptosis, and infarct size after ischemia-reperfusion in vivo.”
Oxidative stress and regulated cell death in Parkinson’s disease
Dionísio, P. A., Amaral, J. D., & Rodrigues, C. M. P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101263 · Cited by 443
Apoptotic cell death in disease—Current understanding of the NCCD 2023
Vitale, I., Pietrocola, F., Guilbaud, E., Aaronson, S. A., Abrams, J., Adam, D., Agostini, M., Agostinis, P., Alnemri, E. S., Altucci, L., et al. (2023) · Cell Death and Differentiation · doi:10.1038/s41418-023-01153-w · Cited by 352
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Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition
Bonora, M., Wieckowski, M. R., Chinopoulos, C., Kepp, O., Kroemer, G., Galluzzi, L., & Pinton, P. (2015) · Oncogene · doi:10.1038/onc.2014.96 · Cited by 330
Mitochondria—Judges and Executioners of Cell Death Sentences
Bhola, P. D., & Letai, A. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.019 · Cited by 326
“Surprisingly, loss of BAX and BAK inhibits mitochondrial swelling and rupture following mPTP opening, indicating that some of the proteins involved in mitochondrial-mediated apoptosis may nonetheless affect the mPTP (Karch et al., 2013; Whelan et al., 2012).”
Acetaminophen Hepatotoxicity
Ramachandran, A., & Jaeschke, H. (2019) · Seminars in Liver Disease · doi:10.1055/s-0039-1679919 · Cited by 331
The mitochondrial permeability transition pore and its role in myocardial ischemia reperfusion injury
Ong, S., Samangouei, P., Kalkhoran, S. B., & Hausenloy, D. J. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.11.005 · Cited by 328
“Most recently, Molkentin's laboratory [52] have suggested that Bax/Bak proteins by regulating OMMpermeability are required forMPTP-dependent necrotic cell death.”
Background
RPE necroptosis in response to oxidative stress and in AMD
Hanus, J., Anderson, C. A., & Wang, S. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.09.002 · Cited by 293
Basic Biology of Oxidative Stress and the Cardiovascular System
Sack, M. N., Fyhrquist, F., Saijonmaa, O. J., Fuster, V., & Kovacic, J. C. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.05.034 · Cited by 248
“This is illustrated by the apoptotic OMM proteins BAX and BAK, which appear to be necessary for some forms of cardiac necrosis (38,49).”
Tnf induces pathogenic programmed macrophage necrosis in tuberculosis through a mitochondrial-lysosomal-endoplasmic reticulum circuit
Roca, F. J., Whitworth, L. J., Redmond, S., Jones, A. A., & Ramakrishnan, L. (2019) · Cell · doi:10.1016/j.cell.2019.08.004 · Cited by 233
Molecular identity of the mitochondrial permeability transition pore and its role in ischemia-reperfusion injury
Morciano, G., Giorgi, C., Bonora, M., Punzetti, S., Pavasini, R., Wieckowski, M. R., Campo, G. C., & Pinton, P. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.08.015 · Cited by 232
“These data were confirmed by Molkentin's group, who used genetic background knockout models for Bax and Bak [51].”
BackgroundMethod
Mitochondrial Ca2+ and regulation of the permeability transition pore
Hurst, S., Hoek, J. B., & Sheu, S. (2016) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-016-9672-x · Cited by 227
“However, the IMM mPTP machinery was still functional and the protection was attributed to preventing OMM rupture and release of IMS components (Whelan et al. 2012; Karch et al. 2013).”
Background
Mitochondrial Permeability Transition: New Findings and Persisting Uncertainties
Izzo, V., Bravo-San Pedro, J. M., Sica, V., Kroemer, G., & Galluzzi, L. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.04.006 · Cited by 205
“Moreover, mice lacking specifically Bax and Bak1 in cardiomyocytes have been attributed an increased resistance to cardiac ischemia/reperfusion, as compared to their wild-type littermates, and isolated Bax / Bak1 / mitochondria were unable to normally undergo MPT in vitro [40].”
Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives
Ramachandran, A., & Jaeschke, H. (2017) · Gene Expression · doi:10.3727/105221617x15084371374138 · Cited by 215
Oxidative stress induces mitochondrial iron overload and ferroptotic cell death
Chen, Y., Guo, X., Zeng, Y., Mo, X., Hong, S., He, H., Li, J., Fatima, S., & Liu, Q. (2023) · Scientific Reports · doi:10.1038/s41598-023-42760-4 · Cited by 202
Non-apoptotic functions of BCL-2 family proteins
Gross, A., & Katz, S. G. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.22 · Cited by 202
“Moreover, this does not appear to be dependent on their ability to oligomerize and undergo MOMP as an oligomerization-deficient BAXmutant still permitsMPTPdependent mitochondrial swelling and necrotic cell death.(22,23) The mechanism by which BAX and BAK promote MPTP is still under investigation, with some data suppor…”
Background
Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration
Abdullah, C. S., Alam, S., Aishwarya, R., Miriyala, S., Bhuiyan, M. A. N., Panchatcharam, M., Pattillo, C. B., Orr, A. W., Sadoshima, J., Hill, J. A., et al. (2019) · Scientific Reports · doi:10.1038/s41598-018-37862-3 · Cited by 197
The Mitochondrial Permeability Transition Pore and Cancer: Molecular Mechanisms Involved in Cell Death
Bonora, M., & Pinton, P. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00302 · Cited by 208
“In particular, the proapoptotic members Bax and Bcl-2 homologous antagonist killer (Bak) have a dramatic positive effect on mPTP opening, as confirmed in bax and bak knockout models (34).”
Background
The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome
Dorn, G. W., & Kitsis, R. N. (2014) · Circulation Research · doi:10.1161/circresaha.116.303554 · Cited by 193
“Some data suggest that Bax on the outer mitochondrial membrane is in complex with MPTP.99 Another mechanism that the Kitsis group has explored is that Bax facilitates necrosis through its previously recognized ability to promote mitochondrial fusion.100,104 Interestingly, oligomerization-deficient Bax mutants, the sam…”
BackgroundInfluential
Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives
Ramachandran, A., Duan, L., Akakpo, J. Y., & Jaeschke, H. (2018) · Journal of Clinical and Translational Research · doi:10.18053/jctres.04.201801.005 · Cited by 188
“Analysis of molecular mediators involved in mitochondrial MPT pore opening indicated that diclofenac induced early activation of Bax and Bak in immortalized human hepatocytes (HC-04), and caused mitochondrial translocation of Bax [106].”
Background
Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets
Briston, T., Selwood, D. L., Szabadkai, G., & Duchen, M. R. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.11.004 · Cited by 190
“Outer membrane components, the voltage-dependent anion channel (VDAC) [15] and BCL-2 family members BAK/BAX [20] have further been suggested to play a role as modulators of pore opening.”
Background
Cancer Metabolism and the Evasion of Apoptotic Cell Death
Sharma, A., Boise, L., & Shanmugam, M. (2019) · Cancers · doi:10.3390/cancers11081144 · Cited by 202
“Further, BAX and BAK are involved in the process of mitochondrial permeability transition pore (MPTP) formation in necrosis [145,146].”
Background
Mitochondrial permeability transition pore-dependent necrosis
Robichaux, D. J., Harata, M., Murphy, E., & Karch, J. M. (2022) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2022.11.003 · Cited by 197
Self-citation
Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy
Kwong, J. Q., Davis, J., Baines, C. P., Sargent, M. A., Karch, J., Wang, X., Huang, T., & Molkentin, J. D. (2014) · Cell Death & Differentiation · doi:10.1038/cdd.2014.36 · Cited by 174
“Structurally, the MPTP complex has been proposed to be comprised of the ATP synthase(17,18) and to be regulated by cyclophilin D (CypD),(19,20) ANT,(21) and the pro-apoptotic proteins Bax and Bak in the outer mitochondrial membrane.(22,23) PiC has also been suggested to be an inner-membrane component of the MPTP becau…”
BackgroundMethodSelf-citation
Role of apoptosis and autophagy in tuberculosis
Lam, A., Prabhu, R., Groß, C., Riesenberg, L. A., Singh, V., & Aggarwal, S. (2017) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00162.2017 · Cited by 182
“Beclin 1 can also influence apoptosis and necrosis of cells AJP-Lung Cell Mol Physiol • doi:10.1152/ajplung.00162.2017 • www.ajplung.org through its interactions with the B-cell lymphoma-2 (BCL2) family of proteins, BCL2-associated X protein (BAX) and BCL2-antagonistic/killer (BAK; 53, 54, 138).”
BackgroundInfluential
Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology
Ramachandran, A., & Jaeschke, H. (2017) · Journal of Clinical and Translational Research · doi:10.18053/jctres.03.2017s1.002 · Cited by 165
“Bak form the components of the mitochondrial permeability transition pore (MPTP) in the outer membrane [90,91], the”
Background
The mitochondrial permeability transition pore: an evolving concept critical for cell life and death
Morciano, G., Naumova, N., Koprowski, P., Valente, S. A., Sardão, V. A., Potes, Y., Rimessi, A., Wieckowski, M. R., & Oliveira, P. J. (2021) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12764 · Cited by 161
“(2013) provided evidence for B-cell lymphoma-2 (Bcl-2)-associated X (Bax) and Bcl-2-antagonist/killer 1 (Bak) members of the Bcl-2 family as mPTP components; using transgenic animal models, they demonstrated that the absence of both proteins promoted resistance to mitochondrial swelling and resulted in the lack of cha…”
Background
Regulated Necrotic Cell Death
Karch, J. M., & Molkentin, J. D. (2015) · Circulation Research · doi:10.1161/circresaha.116.305421 · Cited by 164
Self-citation
Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane
Zhang, M., Zheng, J., Nussinov, R., & Ma, B. (2017) · Scientific Reports · doi:10.1038/s41598-017-02825-7 · Cited by 160
Dissecting the molecular pathophysiology of drug-induced liver injury
Ye, H., Nelson, L. J., del Moral, M. G., Martínez-Naves, E., & Cubero, F. J. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i13.1373 · Cited by 157
Anticancer potential of bioactive peptides from animal sources
Wang, L., Dong, C., Li, X., Han, W., & Su, X. (2017) · Oncology Reports · doi:10.3892/or.2017.5778 · Cited by 139
Differential regulation of autophagy and mitophagy in pulmonary diseases
Aggarwal, S., Mannam, P., & Zhang, J. (2016) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00128.2016 · Cited by 137
Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology
Bonora, M., Patergnani, S., Ramaccini, D., Morciano, G., Pedriali, G., Kahsay, A., Bouhamida, E., Giorgi, C., Wieckowski, M., & Pinton, P. (2020) · Biomolecules · doi:10.3390/biom10070998 · Cited by 135
“Bax and Bak are also required for PTPC-dependent necrotic cell death; in fact, the loss of Bax/Bak resulted in resistance to mitochondrial calcium overload and swelling [49].”
Background
The mitochondrial permeability transition: Recent progress and open questions
Bernardi, P., Carraro, M., & Lippe, G. (2021) · FEBS Journal · doi:10.1111/febs.16254 · Cited by 150
Control of mitochondrial physiology and cell death by the Bcl-2 family proteins Bax and Bok
D’Orsi, B., Mateyka, J., & Prehn, J. H. M. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.03.010 · Cited by 134
“…including Bcl-2 and Bcl-xL, have been suggested to modulate the mPTP by maintaining it in a close conformation, while pro-apoptotic proteins, such as Bax and Bak, engage ANTand/ or VDAC to induce mPTP opening (Marzo et al., 1998; Shimizu et al., 1999; Whelan et al., 2012; Karch et al., 2013).”
Bisphenol A-induced metabolic disorders: From exposure to mechanism of action
Akash, M. S. H., Sabir, S., & Rehman, K. (2020) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2020.103373 · Cited by 136
Identifying the components of the elusive mitochondrial permeability transition pore
Karch, J. M., & Molkentin, J. D. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1410104111 · Cited by 134
Self-citation
Mechanisms of Regulated Cell Death: Current Perspectives
Santagostino, S. F., Assenmacher, C., Tarrant, J. C., Adedeji, A. O., & Radaelli, E. (2021) · Veterinary Pathology · doi:10.1177/03009858211005537 · Cited by 137
A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy
Amgalan, D., Garner, T. P., Pekson, R., Jia, X. F., Yanamandala, M., Paulino, V. M., Liang, F. G., Corbalan, J. J., Lee, J., Chen, Y., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0039-1 · Cited by 132
Inhibition of the mPTP and Lipid Peroxidation Is Additively Protective Against I/R Injury
Mendoza, A., Patel, P., Robichaux, D. J., Ramirez, D., & Karch, J. M. (2024) · Circulation Research · doi:10.1161/circresaha.123.323882 · Cited by 131
“18 19–21 This lack of translatable protection may be explained by potential compensatory forms of cell death during I/R, as many forms of cell death have been hypothesized to occur during this injury.”
BackgroundSelf-citation
The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation
Ouyang, W., Wang, S., Yan, D., Wu, J., Zhang, Y., Li, W. S., Hu, J., & Liu, Z. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01624-z · Cited by 135
“To explore the role of mPTP in the activation of the cGASSTING pathway, cyclosporin A (CsA), a mPTP inhibitor, was used to block mPTP opening.(46,47) HS-induced mPTP opening was reversed (Fig.”
Method
Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]
Fernández-Checa, J. C., Bagnaninchi, P., Ye, H., Sancho‐Bru, P., Falcón‐Pérez, J. M., Royo, F., García‐Ruiz, C., Konu, Ö., Miranda, J. P., Lunov, O., et al. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.06.021 · Cited by 131
“…outer membrane and allowing the exit of molecules less than 1,500 Da, including cytochrome c, apoptosis inducing factor (AIF) and endonuclease G. 46 Although release of cytochrome c and AIF is a hallmark of apoptosis, as they activate caspase 3/7 and lead to nuclear DNA cleavage, respectively,…”
Background
Mitochondrial pores at the crossroad between cell death and inflammatory signaling
Flores‐Romero, H., Dadsena, S., & García‐Sáez, A. J. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.02.021 · Cited by 131
Targeted Deletion of p53 in the Proximal Tubule Prevents Ischemic Renal Injury
Yuan, Y., Kim, J., Westphal, S. N., Long, K. E., & Padanilam, B. J. (2014) · Journal of the American Society of Nephrology · doi:10.1681/asn.2013121270 · Cited by 121
Intersections between Regulated Cell Death and Autophagy
Napoletano, F., Baron, O., Vandenabeele, P., Mollereau, B., & Fanto, M. (2019) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.12.007 · Cited by 120
Mitochondria as Potential Targets and Initiators of the Blue Light Hazard to the Retina
Tao, J., Zhou, W., & Zhu, X.-G. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/6435364 · Cited by 125
“In addition, in some cases of apoptosis, the opening of the mPTP also contributes to mitochondrial swelling and rupture, as well as to necrotic cell death, which is regulated by Bax/Bak and cyclophilin D (CypD) [192, 193].”
Background
Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis?
Yuan, Y., & Padanilam, B. J. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2202-5 · Cited by 122
“These data suggest that the MPTP is an IMM-regulated process, although in the absence of Bax/ Bak, the OMM resists swelling and prevents organelle rupture, which prevents necrosis [17].”
BackgroundInfluential
Mitochondrial–Lysosomal Axis in Acetaminophen Hepatotoxicity
Moles, A., Torres, S., Baulies, A., García‐Ruiz, C., & Fernández-Checa, J. C. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00453 · Cited by 116
“The onset of MPT is characterized by the permeabilization of the MOM secondary to a sudden increase in permeability of the MIM, which allows the exit of molecules less than 1500 Da (Karch et al., 2013).”
Background
Small-molecule allosteric inhibitors of BAX
Garner, T. P., Amgalan, D., Reyna, D. E., Li, S., Kitsis, R. N., & Gavathiotis, E. (2019) · Nature Chemical Biology · doi:10.1038/s41589-018-0223-0 · Cited by 105
Cardiolipin Promotes Pore-Forming Activity of Alpha-Synuclein Oligomers in Mitochondrial Membranes
Ghio, S., Camilleri, A., Caruana, M., Ruf, V., Schmidt, F., Leonov, A., Ryazanov, S., Griesinger, C., Cauchi, R. J., Kamp, F., et al. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00320 · Cited by 108
ARC regulates programmed necrosis and myocardial ischemia/reperfusion injury through the inhibition of mPTP opening
Xu, T., Ding, W., Ao, X., Chu, X., Wan, Q., Wang, Y., Xiao, D., Yu, W., Li, M., Yu, F., et al. (2018) · Redox Biology · doi:10.1016/j.redox.2018.10.023 · Cited by 102
Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death
Karch, J. M., Kanisicak, O., Brody, M. J., Sargent, M. A., Michael, D. M., & Molkentin, J. D. (2015) · PLoS ONE · doi:10.1371/journal.pone.0130520 · Cited by 106
“Ppif MEFs are partially resistant to necrosis induced by ionomycin or H2O2, but not against apoptosis induced by staurosporine [3, 4, 6].”
BackgroundMethodInfluentialSelf-citation
Nanoparticle‐Mediated Delivery of Mitochondrial Division Inhibitor 1 to the Myocardium Protects the Heart From Ischemia‐Reperfusion Injury Through Inhibition of Mitochondria Outer Membrane Permeabilization: A New Therapeutic Modality for Acute Myocardial Infarction
Ishikita, A., Matoba, T., Ikeda, G., Koga, J., Mao, Y., Nakano, K., Takeuchi, O., Sadoshima, J., & Egashira, K. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.116.003872 · Cited by 108
“Karch et al.(39) recently demonstrated that inhibition of MOMP by Bax and Bak”
Background
A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage
Vázquez, J. M., Sulak, M. A., Chigurupati, S., & Lynch, V. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.042 · Cited by 102
Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice
Belizário, J. E., Cordeiro, L., & Enns, S. C. (2015) · Mediators of Inflammation · doi:10.1155/2015/128076 · Cited by 106
“In light on these results, the authors concluded that Bax/Bak oligomers within the outer membrane are required for mitochondrial permeability pore-dependent cell death by serving as a necessary functional component of the MPTP [106].”
BackgroundResultInfluential
Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases
Simmons, E. C., Scholpa, N. E., & Schnellmann, R. G. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113309 · Cited by 100
“The mPTP is a key effector in the pathway to cell death (Baines et al., 2003; Karch et al., 2013; Karch and Molkentin, 2014; Xu et al., 2019) in that opening of the mPTP further exacerbates mitochondrial dysfunction (Baines et al.”
Background
Caspases in the Developing Central Nervous System: Apoptosis and Beyond
Nguyen, T. T. M., Gillet, G., & Popgeorgiev, N. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.702404 · Cited by 104
Role of Mitochondria in Retinal Pigment Epithelial Aging and Degeneration
Tong, Y., Zhang, Z., & Wang, S. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.926627 · Cited by 102
Cyclophilin D and myocardial ischemia–reperfusion injury: A fresh perspective
Alam, M. R., Baetz, D., & Ovize, M. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.09.026 · Cited by 101
“components of the OMM are still known to contribute to its induction [42,69].”
Background
Innate sensing of picornavirus infection involves cGAS-STING-mediated antiviral responses triggered by mitochondrial DNA release
Liu, H., Zhu, Z., Xue, Q., Yang, F., Li, Z., Xue, Z., Cao, W., He, J., Guo, J., Liu, X., et al. (2023) · PLoS Pathogens · doi:10.1371/journal.ppat.1011132 · Cited by 96
“mPTP is located at the inner mitochondrial membrane, while VDAC1 and Bak/Bax are located at the outer mitochondrial membrane [41,42].”
Background
A mitochondrial journey through acetaminophen hepatotoxicity
Ramachandran, A., & Jaeschke, H. (2020) · Food and Chemical Toxicology · doi:10.1016/j.fct.2020.111282 · Cited by 95
“For example, activation of the inner membrane permeability transition and loss of mitochondrial membrane potential can occur in absence of Bax and Bak (Karch et al., 2013), and Bax has been shown to form two distinct types of channels which can fine-tune outer membrane permeabilization (Lin et al.”
BackgroundInfluential
Ca 2+ toxicity and mitochondrial damage in acute pancreatitis: translational overview
Maléth, J., & Hegyi, P. J. (2016) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2015.0425 · Cited by 92
Autophagic cell death is dependent on lysosomal membrane permeability through bax and bak
Karch, J., Schips, T. G., Maliken, B. D., Brody, M. J., Sargent, M. A., Kanisicak, O., & Molkentin, J. D. (2017) · eLife · doi:10.7554/elife.30543 · Cited by 91
“…Karch et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. needed for mitochondrial-dependent cellular necrosis (Karch et al., 2013).”
InfluentialSelf-citation
A novel fission-independent role of dynamin-related protein 1 in cardiac mitochondrial respiration
Zhang, H., Wang, P., Bisetto, S., Yoon, Y., Chen, Q., Sheu, S., & Wang, W. (2016) · Cardiovascular Research · doi:10.1093/cvr/cvw212 · Cited by 88
Free radicals, antioxidants, nuclear factor‐E2‐related factor‐2 and liver damage
Ramos‐Tovar, E., & Muriel, P. (2019) · Journal of Applied Toxicology · doi:10.1002/jat.3880 · Cited by 91
“…the synthesis of mitochondrial proteins and increase mitochondrial permeability transition, which in turn allows the efflux of small molecules (Karch et al., 2013), causing mitochondria to become further depolarized, thus reducing the proton gradient leading to the collapse of the…”
Background
Necroptosis: A new way of dying?
Hanson, B. (2016) · Cancer Biology & Therapy · doi:10.1080/15384047.2016.1210732 · Cited by 93
“The essential apoptotic MOMP proteins, BAK and BAX, have been implicated in MPT by Karch et al. 94 to effect necrotic mitochondrial pore-dependent cell death through a mechanism that differs from apoptotic MOMP.94 The effect of mitochondrial disruption is thought to cause ATP-depletion and excessive ROS production to…”
BackgroundInfluential
A 20/20 view of ANT function in mitochondrial biology and necrotic cell death
Bround, M. J., Bers, D. M., & Molkentin, J. D. (2020) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2020.05.012 · Cited by 83
“While subsequent studies have ruled out the requirement of VDAC as a component of the MPTP [125], other work has shown that the ANT c-state can specifically associate with BAX [126], which is consistent with our current understanding of BAX and BAK and their putative role in MPTP-dependent cell death [127].”
Result
HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart
Lam, C. K., Zhao, W., Liu, G.-S., Cai, W.-F., Gardner, G., Adly, G., & Kranias, E. G. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1508760112 · Cited by 80
“Furthermore, the expression levels of Bax and Bak, which were recently suggested to govern the porosity of the mitochondrial outer membrane (22), were not altered by HAX-1 overexpression either.”
Background
Adverse Effects of Perfluorooctane Sulfonate on the Liver and Relevant Mechanisms
Wang, P., Liu, D., Yan, S., Cui, J., Liang, Y., & Ren, S. (2022) · Toxics · doi:10.3390/toxics10050265 · Cited by 84
“ROS-induced oxidative stress can induce the occurrence of mitochondrial permeability transition (MPT) in hepatocytes, which also leads to changes in mitochondrial membrane potential [122,123].”
Background
BNIP3 and Nix: Atypical regulators of cell fate
Field, J. T., & Gordon, J. W. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2022.119325 · Cited by 84
Cardiac Dysfunction in the Sigma 1 Receptor Knockout Mouse Associated With Impaired Mitochondrial Dynamics and Bioenergetics
Abdullah, C. S., Alam, S., Aishwarya, R., Miriyala, S., Panchatcharam, M., Bhuiyan, M. A. N., Peretik, J. M., Orr, A. W., James, J., Osińska, H. E., et al. (2018) · Journal of the American Heart Association · doi:10.1161/jaha.118.009775 · Cited by 77
Self-citation
SENP5, a SUMO isopeptidase, induces apoptosis and cardiomyopathy
Kim, E. Y., Zhang, Y., Beketaev, I., Segura, A. M., Yu, W., Xi, Y. T., Chang, J., & Wang, J. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.08.003 · Cited by 81
“To determine mitochondrial permeability transition pore (MPTP) activation, cardiac mitochondria were isolated by differential centrifugation [33,34].”
Method
Melatonin and Ischemic Stroke: Mechanistic Roles and Action
Andrabi, S. S., Parvez, S., & Tabassum, H. (2015) · Advances in Pharmacological Sciences · doi:10.1155/2015/384750 · Cited by 77
“Bcl-2 associated proteins contain various antiapoptotic proteins (bcl-2, bcl-xl) and proapoptotic proteins (bax, bak) which are prime regulators of apoptosis and necrotic death [50–52].”
Background
Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion
Carinci, M., Vezzani, B., Patergnani, S., Ludewig, P., Lessmann, K., Magnus, T. U., Casetta, I., Pugliatti, M., Pinton, P., & Giorgi, C. (2021) · Biomedicines · doi:10.3390/biomedicines9020169 · Cited by 80
“Of note, loss of the proapoptotic proteins BAK and BAX has been shown to reduce mitochondrial membrane permeability, resulting in resistance to mitochondrial calcium overload and necrotic cell death [74].”
Background
Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasisPreprint
Tuzlak, S., Kaufmann, T., & Villunger, A. (2016) · Genes & Development · doi:10.1101/gad.289298.116 · Cited by 73
“Also, in tissues with a low proliferative index, like the brain (Ren et al. 2010), heart, and liver (Whelan et al. 2012; Karch et al. 2013), BAX and BAK seem dispensable for homeostasis, as their codeletion does not seem to trigger a hyperplastic phenotype in these organs (Table 2).”
BackgroundInfluential
Mitochondrial involvement in myocyte death and heart failure
Goldenthal, M. J. (2016) · Heart Failure Reviews · doi:10.1007/s10741-016-9531-1 · Cited by 73
“Strikingly, triple knockout mice lacking Bax/Bak and cyclophilin D, the key regulator of mPTP opening and necrotic cell death, failed to display any further reduction in infarct size over those deficient in Bax/Bak suggesting that Bax and Bak regulate necrosis in vivo and confirming a connection between mitochondrial…”
Influential
The still uncertain identity of the channel-forming unit(s) of the mitochondrial permeability transition pore
Baines, C. P., & Gutiérrez‐Aguilar, M. (2018) · Cell Calcium · doi:10.1016/j.ceca.2018.05.003 · Cited by 72
“The role of Bax as an MPT pore component has been considered in some studies proposing that Bax and Bak may behave as the mitochondrial outer membrane component of the MPT pore [44].”
Background
Ca2+ signaling and cell death
Dhaouadi, N., Vitto, V. A. M., Pinton, P., Galluzzi, L., & Marchi, S. (2023) · Cell Calcium · doi:10.1016/j.ceca.2023.102759 · Cited by 72
“Accordingly, BAX and BAK1 have been involved in RCD modalities other than apoptosis [74,75].”
Acetaminophen hepatotoxicity: A mitochondrial perspective
Ramachandran, A., & Jaeschke, H. (2019) · Advances in pharmacology · doi:10.1016/bs.apha.2019.01.007 · Cited by 77
“While the components of the MPTP on the inner membrane other than cyclophilin D are still being characterized, it is well recognized that the outer membrane components are composed of Bax, along with the protein Bak on the mitochondrial outer membrane (Karch et al., 2013; Karch et al., 2014).”
Regulation of cell death in the cardiovascular system
Patel, P., & Karch, J. M. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.11.005 · Cited by 74
Self-citation
Mitochondrial Mechanisms of Necroptosis in Liver Diseases
Xue, C., Gu, X., Li, G., Bao, Z., & Li, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010066 · Cited by 70
“reported that BCL-2 family members are also required for mitochondrial pore-dependent necrotic cell death by facilitating outer membrane permeability of the MPTP [70].”
Background
BCL2 Family, Mitochondrial Apoptosis, and Beyond
Dai, H., Meng, W., & Kaufmann, S. H. (2016) · Cancer translational medicine · doi:10.4103/2395-3977.177558 · Cited by 72
Oxidant Stress and Lipid Peroxidation in Acetaminophen Hepatotoxicity
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Excitotoxicity Revisited: Mitochondria on the Verge of a Nervous Breakdown
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Necroptosis in heart disease: Molecular mechanisms and therapeutic implications
Guo, X., Chen, Y., & Liu, Q. (2022) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2022.05.006 · Cited by 70
Programmed necrosis in cardiomyocytes: mitochondria, death receptors and beyond
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“Recently, double-knockout genetic experiments confirmed and extended the involvement of Bax and Bak, which are known as pro-apoptotic proteins, in mPTP action and in necrotic cell death (Karch et al., 2013).”
Background
Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax
Jensen, K. M., WuWong, D. J., Wong, S., Matsuyama, M., & Matsuyama, S. (2019) · Experimental Biology and Medicine · doi:10.1177/1535370219833624 · Cited by 61
A Bak-dependent mitochondrial amplification step contributes to Smac mimetic/glucocorticoid-induced necroptosis
Rohde, K., Kleinesudeik, L., Roesler, S., Löwe, O., Heidler, J., Schröder, K., Wittig, I., Dröse, S., & Fulda, S. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2016.102 · Cited by 60
“During necrotic cell death, Bax and Bak as outer membrane components have been shown to promote mitochondrial swelling and rupture upon opening of the mitochondrial permeability transition pore (MPTP) by facilitating outer membrane permeability.(31) Opening of the MPTP, a channel in the inner mitochondrial membrane th…”
Background

Authors: Karch, J., Kwong, J. Q., Burr, A. R., Sargent, M. A., Elrod, J. W., Peixoto, P. M., Martinez-Caballero, S., Osinska, H., Cheng, E. H.-Y., Robbins, J., Kinnally, K. W., & Molkentin, J. D.
Affiliations: Cincinnati Children's Hospital Medical Center (US)
New York University (US)
Department of Basic Sciences, New York University College of Dentistry, New York, United States
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States
Memorial Sloan Kettering Cancer Center (US)
Corresponding author: Molkentin, Jeffery D
ORCID: Karch, Jason
Kwong, Jennifer Q
Sargent, Michelle A
Elrod, John W
Peixoto, Pablo M
Cheng, Emily H-Y
Robbins, Jeffrey
Molkentin, Jeffery D
Venue: eLife
Publisher: eLife Sciences Publications, Ltd
Published: 2013-08-27
Volume: 2
Pages: e00772-e00772
ISSN: 2050-084X (ISSN-L)
DOI: 10.7554/elife.00772
PMC: PMC3755340
OpenAlex: W2139284714
Cited by: 290
References: 53
Citations by year: 2026: 8 · 2025: 25 · 2024: 16 · 2023: 31 · 2022: 22 · 2021: 26 · 2020: 25 · 2019: 23 · 2018: 27 · 2017: 22 · 2016: 26 · 2015: 16 · 2014: 21 · 2013: 1
FWCI: 9.55
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/3.0/ (vor)
creativecommons.org/licenses/by/3.0/ (am)
creativecommons.org/licenses/by/3.0/ (tdm)
Locations: eLife (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
CUNY Academic Works (City University of New York) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Howard Hughes Medical Institute
National Institutes of Health (P01 HL080101)
American Heart Association pre-doctoral grant
American Heart Association
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
Keywords: Bax, Bak, mitochondrial permeability transition pore, necrosis, mitochondrial outer membrane permeabilization, Bcl-2 family proteins, mitochondrial calcium overload, mitochondrial swelling, ischemia, Bax oligomerization
MeSH terms: Mitochondrial Permeability Transition Pore, Animals, Necrosis, Mitochondrial Membrane Transport Proteins, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mice

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Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice

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