Advancing Treatment in Atopic Dermatitis: A Comprehensive Review of Clinical Efficacy, Safety, and Comparative Insights Into Corticosteroids, Calcineurin Inhibitors, and Phosphodiesterase-4 Inhibitors as Topical Therapies.

Atopic dermatitis (AD) is a pervasive and multifaceted dermatological disorder causing daily distress to afflicted individuals worldwide. This comprehensive review synthesizes the historical and contemporary advancements in therapeutic strategies, offering a critical analysis of their efficacy, safety profiles, and adaptability. The enduring role of topical corticosteroids in managing AD is examined, acknowledging their potent anti-inflammatory properties alongside their potential adverse side effects, particularly in extended usage. The article explores the utilization of topical calcineurin inhibitors like tacrolimus and pimecrolimus, highlighting their novel anti-inflammatory pathways while also scrutinizing concerns over potential malignancies that relegate them to second-line therapy. The present investigation features the emergence of crisaborole, a phosphodiesterase four inhibitor. Its innovative mode of action, benign safety profile, and applicability to mild and moderate AD are thoroughly evaluated. The review also includes challenges, particularly cost considerations, which constrain accessibility and necessitate nuanced implementation in therapeutic regimens. This study underscores the need for persistent investigation, teamwork, and innovations in managing AD. In this regard, AD requires a united approach between clinicians, researchers, affected individuals, and policymakers to refine patient-focused treatment and develop precise, economical strategies to address this chronic and frequently life-altering health condition.

Interstitial lung abnormalities and interstitial lung diseases associated with cigarette smoking in a rural cohort undergoing surgical resection.

BACKGROUND: Cigarette smoking is a risk factor for interstitial lung abnormalities (ILAs) and interstitial lung diseases (ILDs). Investigation defining the relationships between ILAs/ILDs and clinical, radiographic, and pathologic findings in smokers have been incomplete. Employing a cohort undergoing surgical resection for lung nodules/masses, we (1) define the prevalence of ILAs/ILDs, (2) delineate their clinical, radiographic and pathologic predictors, and (3) determine their associations with mortality. METHODS: Patients undergoing resection of lung nodules/masses between 2017 and 2020 at a rural Appalachian, tertiary medical center were retrospectively investigated. Predictors for ILAs/ILDs and mortality were assessed using multivariate logistic regression analysis. RESULTS: In the total study cohort of 352 patients, radiographic ILAs and ILDs were observed in 35.2% and 17.6%, respectively. Among ILA patterns, subpleural reticular changes (14.8%), non-emphysematous cysts, centrilobular (CL) ground glass opacities (GGOs) (8% each), and mixed CL-GGO and subpleural reticular changes (7.4%) were common. ILD patterns included combined pulmonary fibrosis emphysema (CPFE) (3.1%), respiratory bronchiolitis (RB)-ILD (3.1%), organizing pneumonitis (2.8%) and unclassifiable (4.8%). The group with radiographic ILAs/ILDs had a significantly higher proportion of ever smokers (49% vs. 39.9%), pack years of smoking (44.57 ± 36.21 vs. 34.96 ± 26.22), clinical comorbidities of COPD (35% vs. 26.5%) and mildly reduced diffusion capacity (% predicated 66.29 ± 20.55 vs. 71.84 ± 23). Radiographic centrilobular and paraseptal emphysema (40% vs. 22.2% and 17.6% vs. 9.6%, respectively) and isolated traction bronchiectasis (10.2% vs. 4.2%) were associated with ILAs/ILDs. Pathological variables of emphysema (34.9% vs. 18.5%), any fibrosis (15.9% vs. 4.6%), peribronchiolar metaplasia (PBM, 8% vs. 1.1%), RB (10.3% vs. 2.5%), and anthracosis (21.6% vs. 14.5%) were associated with ILAs/ILDs. Histologic emphysema showed positive correlations with any fibrosis, RB, anthracosis and ≥ 30 pack year of smoking. The group with ILAs/ILDs had significantly higher mortality (9.1% vs. 2.2%, OR 4.13, [95% CI of 1.84-9.25]). CONCLUSIONS: In a rural cohort undergoing surgical resection, radiographic subclinical ILAs/ILDs patterns were highly prevalent and associated with ever smoking and intensity of smoking. The presence of radiographic ILA/ILD patterns and isolated honeycomb changes were associated with increased mortality. Subclinical ILAs/ILDs and histologic fibrosis correlated with clinical COPD as well as radiographic and pathologic emphysema emphasizing the co-existence of these pulmonary injuries in a heavily smoking population.

Coagulation Studies Are Not Predictive of Hematological Complications of COVID-19 Infection.

Objectives Thrombotic and bleeding complications are common in COVID-19 disease. In a prospective study, we performed a comprehensive panel of tests to predict the risk of bleeding and thrombosis in patients admitted with hypoxic respiratory failure due to severe COVID-19 infection. Methods We performed a single center (step down and intensive care unit [ICU] at a quaternary care academic hospital) prospective study. Sequentially enrolled adult (≥18 years) patients were admitted with acute hypoxic respiratory failure due to COVID-19 between June 2020 and November 2020. Several laboratory markers of coagulopathy were tested after informed and written consent. Results Thirty-three patients were enrolled. In addition to platelet counts, prothrombin time, and activated partial thromboplastin time, a series of protocol laboratories were collected within 24 hours of admission. These included Protein C, Protein S, Antithrombin III, ADAMTS13, fibrinogen, ferritin, haptoglobin, and peripheral Giemsa smear. Patients were then monitored for the development of hematological (thrombotic and bleeding) events and followed for 30 days after discharge. Twenty-four patients (73%) required ICU admissions. At least one laboratory abnormality was detected in 100% of study patients. Nine patients (27%) suffered from significant hematological events, and four patients had a clinically significant bleeding event requiring transfusion. No significant association was observed between abnormalities of coagulation parameters and the incidence of hematologic events. However, a higher SOFA score (10.89 ± 3.48 vs. 6.92 ± 4.10, p = 0.016) and CKD (5/9 [22.2%] vs. 2/24 [12.5%] p = 0.009) at baseline were associated with the development of hematologic events. 33.3% of patients died at 30 days. Mortality was similar in those with and without hematological events. Reduced ADAMTS13 level was significantly associated with mortality. Conclusion Routine extensive testing of coagulation parameters did not predict the risk of bleeding and thrombosis in COVID-19 patients. Thrombotic and bleeding events in COVID-19 patients are not associated with a higher risk of mortality. Interestingly, renal dysfunction and a high SOFA score were found to be associated with increased risk of hematological events.

Defining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase.

F-ATP synthase is a leading candidate as the mitochondrial permeability transition pore (PTP) but the mechanism(s) leading to channel formation remain undefined. Here, to shed light on the structural requirements for PTP formation, we test cells ablated for g, OSCP and b subunits, and ρ0 cells lacking subunits a and A6L. Δg cells (that also lack subunit e) do not show PTP channel opening in intact cells or patch-clamped mitoplasts unless atractylate is added. Δb and ΔOSCP cells display currents insensitive to cyclosporin A but inhibited by bongkrekate, suggesting that the adenine nucleotide translocator (ANT) can contribute to channel formation in the absence of an assembled F-ATP synthase. Mitoplasts from ρ0 mitochondria display PTP currents indistinguishable from their wild-type counterparts. In this work, we show that peripheral stalk subunits are essential to turn the F-ATP synthase into the PTP and that the ANT provides mitochondria with a distinct permeability pathway.

The Implementation of Protocol-Based Utilization of Neuromuscular Blocking Agent Using Clinical Variables in Acute Respiratory Distress Syndrome Patients.

OBJECTIVES: The recent conflicting data on the mortality benefit of neuromuscular blocking agents in acute respiratory distress syndrome and the potential adverse effects of continuous neuromuscular blocking agent necessitates that these medications should be used judiciously with dose reduction in mind. The aims of the study were to improve the process of care by provider education of neuromuscular blocking agent titration and monitoring and to determine the impact of clinical endpoint based neuromuscular blocking agent titration protocol. DESIGN: We conducted a proof-of-concept historically controlled study of protocol-based intervention standardizing paralytic monitoring and titration using clinical variables. Education of the protocol was provided to ICU staff via bedside teaching and workshops. The primary outcomes were the time to reach goal paralysis and cumulative neuromuscular blocking agent dose. Secondary outcomes included maintenance of deeper sedation (Richmond Agitation and Sedation Scale -5) prior to neuromuscular blocking agent initiation, total time on mechanical ventilation, length of stay, and mortality. SETTING: Medical ICU at a quaternary academic hospital between March 2019 and June 2020. PATIENTS: Adult severe acute respiratory distress syndrome (Pao2/Fio2 <150) patients requiring neuromuscular blocking agent for greater than or equal to 12 hours. Eighty-two patients fulfilled inclusion criteria, 46 in the control group and 36 in the intervention group. INTERVENTIONS: Education and implementation of standardized protocol. MEASUREMENTS AND MAIN RESULTS: Compared with the control group, the time to reach goal paralysis in the intervention group was shorter (8.55 ± 9.4 vs 2.63 ± 5.9 hr; p < 0.0001) on significantly lower dose of cisatracurium (total dose 1,897.96 ± 1,241.0 vs 562.72 ± 546.7 mg; p < 0.0001 and the rate 5.84 ± 2.66 vs 1.99 ± 0.95 µg/kg/min; p < 0.0001). Deeper sedation was achieved at the time of initiation of neuromuscular blocking agent in the intervention arm (mean Richmond Agitation and Sedation Scale -3.3 ± 1.9 vs -4.3 ± 1.7; p = 0.015). There was no significant difference in total time on mechanical ventilation, length of ICU stay, length of hospital stay, and mortality between the two groups. CONCLUSIONS: Implementation of comprehensive education, standardization of sedation prior to neuromuscular blocking agent initiation, integration of clinical variables in determining paralysis achievement, and proper use of peripheral nerve stimulation served as optimal strategies for the titration and monitoring of neuromuscular blocking agent in acute respiratory distress syndrome. This reduced drug utilization while continuing to achieve benefit without causing adverse effects.

The impact of a telemedicine intervention on home non-invasive ventilation in a rural population with advanced COPD.

INTRODUCTION: Rural regions have unique challenges with the implementation of new therapies upon discharge from the hospital due to multiple barriers. OBJECTIVES: We investigated the effect of home non-invasive ventilation (NIV) plus the implementation of a call center following hospitalization for acute exacerbations of COPD (chronic obstructive lung disease) on NIV usage and readmissions. METHODS: In this prospective pilot study, consecutive patients were screened at our institution for diagnosis of hypercarbic respiratory failure or COPD exacerbation from 2018 to 2019. Patients with more than two admissions in the last year were reviewed for eligibility. Of the 82 patients screened, 22 were eligible. There were 10 participants randomized to the intervention (NIV and call center) arm and 10 to NIV alone. RESULTS: A total of 20 patients were randomized (mean age of 64, 45% males, BMI of 32). At three months, average usage was 32.1 days out of 90, 35%. When comparing the call center group to the standard group, there was a statistically significant difference in total days of device usage 48.7 compared to 15.5 (significant U-value of 16, critical value of U at p<.05 of 27) and cumulative use in hours 284 versus 87.7 (significant U-value of 20). Participants in the call center group were readmitted on average 4.2 times compared to 2.4 in the control group which was not statistically different (non-significant U-value of 42). In the follow-up period, 9/20 (45%) of the participants died. CONCLUSION: This pilot study highlights the challenges in implementing care for advanced COPD in a rural population. Our data suggest that telemedicine may favorably address therapy adherence.

Treatment with a triazole inhibitor of the mitochondrial permeability transition pore fully corrects the pathology of sapje zebrafish lacking dystrophin.

High-throughput screening identified isoxazoles as potent but metabolically unstable inhibitors of the mitochondrial permeability transition pore (PTP). Here we have studied the effects of a metabolically stable triazole analog, TR001, which maintains the PTP inhibitory properties with an in vitro potency in the nanomolar range. We show that TR001 leads to recovery of muscle structure and function of sapje zebrafish, a severe model of Duchenne muscular dystrophy (DMD). PTP inhibition fully restores the otherwise defective respiration in vivo, allowing normal development of sapje individuals in spite of lack of dystrophin. About 80 % sapje zebrafish treated with TR001 are alive and normal at 18 days post fertilization (dpf), a point in time when not a single untreated sapje individual survives. Time to 50 % death of treated zebrafish increases from 5 to 28 dpf, a sizeable number of individuals becoming young adults in spite of the persistent lack of dystrophin expression. TR001 improves respiration of myoblasts and myotubes from DMD patients, suggesting that PTP-dependent dysfunction also occurs in the human disease and that mitochondrial therapy of DMD with PTP-inhibiting triazoles is a viable treatment option.

Electronic Cigarettes and Vaping-Associated Lung Injury (EVALI): A Rural Appalachian Experience.

Background: Electronic cigarette use has increased dramatically since their introduction in 2007. Respiratory complications, particularly lipoid pneumonia, have been reported as early as 2012. An outbreak of pulmonary injury in 2019 has been reported in patients using vaping products.Research Question: To describe a rural Appalachian tertiary center's experience of EVALI and to identify novel mechanisms of pulmonary injury patterns.Study Design and Methods: We present a consecutive case series of 17 patients admitted to our rural, academic, tertiary care institution with EVALI from August 2019 to March 2020. Demographics, baseline characteristics, co-morbidities, vaping behavior, and hospital course were recorded. Broncho-alveolar lavage specimens were assessed for lipid-laden macrophages and hemosiderin-laden macrophages with stains for Oil-Red-O (n = 15) and Prussian Blue (n = 14) respectively.The patient volunteered e-liquid materials (n = 6), and vapors were analyzed using a proton transfer reaction time-of-flight mass spectrometer (PTR-TOF-MS) to describe the chemical profile. Post-discharge interviews were conducted.Results: The most common CT finding was bilateral ground-glass opacities with a predilection for lower lung zones. The most frequent pulmonary injury pattern was lipoid pneumonia. The majority of EVALI patients were critically ill requiring ventilation or ECMO. The most severely ill patients were noted to be positive for iron stains in macrophages and showed higher volatile organic compound (VOC) levels in chemical analysis.Interpretation: Based on our experience, EVALI in rural Appalachia presented with relatively severe respiratory failure. Worse outcomes appear to be correlated to high levels of VOCs, iron deposition in lungs, and concomitant infection.

The Unique Cysteine of F-ATP Synthase OSCP Subunit Participates in Modulation of the Permeability Transition Pore.

The mitochondrial permeability transition pore (PTP) is a Ca2+-activated channel that plays a key role in cell death. Thiol oxidation facilitates PTP opening, yet the targets and molecular mechanisms still await a definition. Here, we investigate the role of C141 of F-ATP synthase oligomycin sensitivity conferral protein (OSCP) subunit in PTP modulation by oxidation. We find that the OSCP C141S mutation confers resistance to PTP opening and cell death by diamide and MitoParaquat only when cyclophilin D (CyPD) has been ablated, a protective role that can be explained by CyPD shielding C141 from oxidants. The mutation decreases apoptosis in zebrafish embryos, indicating that this OSCP residue is involved in development. Site-directed mutagenesis in yeast suggests that other conserved cysteines in the α, γ, and c subunits of F-ATP synthase are not involved in PTP modulation. Thus, OSCP provides a strategic site that regulates PTP opening by the interplay between CyPD (un)binding and thiol oxidation-reduction.

Refractory Paraneoplastic Diarrhea Secondary to Adenocarcinoma of the Lung: A Case Report and Literature Review.

Paraneoplastic diarrhea is a commonly described complication of gastrointestinal tract or endocrine malignancies. It is an extremely rare complication of lung adenocarcinoma, with only one previously reported case in the literature. A 46-year-old female with newly diagnosed stage IVb lung adenocarcinoma presented to our intensive care unit in hypovolemic shock with symptoms suggestive of diabetes insipidus (DI) as well as profuse large volume watery diarrhea. Exhaustive serological and microbiological workup revealed the diarrhea to be paraneoplasitc in nature. This case represents the second known case of paraneoplastic diarrhea secondary to lung adenocarcinoma. Clinicians should be aware of this rare phenomenon.

Refractory Acute Respiratory Distress Syndrome Secondary to COVID-19 Successfully Extubated to Average Volume-assured Pressure Support Non-invasive Ventilator.

Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by the highly infectious novel SARS-CoV-2 coronavirus spread by droplet transmission. Consequently, the use of respiratory devices that may potentially promote aerosolization like non-invasive positive pressure ventilation (NIPPV) for diseases such as obstructive sleep apnea (OSA), advanced chronic obstructive lung disease, pulmonary hypertension (PH), and neuromuscular respiratory disease has been called into question. We present a case of a patient with history of OSA and PH convalescing from refractory acute respiratory distress syndrome (ARDS) secondary to COVID-19 who was successfully extubated to average volume-assured pressure support (AVAPS). A 74-year-old male with medical history notable for OSA on NIPPV, PH, and hypertension presented with respiratory failure secondary to COVID-19 confirmed on polymerase chain reaction (PCR) test. His respiratory status worsened leading to ARDS requiring intubation. He was initially extubated to high flow nasal cannula (HFNC) due to hospital policy to avoid NIPPV due to concerns of viral dissemination. He did not tolerate HFNC and required re-intubation for prolonged period. He was then medically optimized for a second attempt and extubated two days later to AVAPS with an anti-viral filter and negative pressure room with a goal of optimizing his critical illness myopathy and pre-existing OSA and PH. He tolerated extubation well, and over the next five days was weaned from alternating AVAPS/HFNC to eventually requiring two liters nasal cannula in the day and AVAPS mode at night. This case highlights a potential therapeutic option for patients with severe respiratory failure secondary to COVID-19. This patient's pre-existing comorbidities of OSA and PH markedly increased his risk for extubation failure on HFNC. The use of AVAPS after his second extubation attempt helped ensure ventilation and oxygenation non-invasively. COVID-19 can lead to prolonged dependence on mechanical ventilation. This pandemic has the potential to create medical resource scarcities, especially in rural areas where ventilators and trained personnel are already in short supply. By using AVAPS mode, this patient was able to rehabilitate his myopathy and participate in intermittent weaning of HFNC to ultimately simple nasal cannula. AVAPS is useful tool to facilitate extubation, as it allows non-invasive support of respiratory dynamics, particularly in those with co-morbidities such as OSA and PH. Further, larger scale studies are needed to determine its exact role during the COVID-19 pandemic.

A novel class of cardioprotective small-molecule PTP inhibitors.

Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.g. cyclosporine A, CsA) targeting cyclophilin D (CyPD) which is a key modulator, but not a structural component of the PTP. This limitation might explain controversial findings in clinical studies. Therefore, we investigated the protective effects against I/R injury of small-molecule inhibitors of the PTP (63 and TR002) that do not target CyPD. Both compounds exhibited a dose-dependent inhibition of PTP opening in isolated mitochondria and were more potent than CsA. Notably, PTP inhibition was observed also in mitochondria devoid of CyPD. Compounds 63 and TR002 prevented PTP opening and mitochondrial depolarization induced by Ca2+ overload and by reactive oxygen species in neonatal rat ventricular myocytes (NRVMs). Remarkably, both compounds prevented cell death, contractile dysfunction and sarcomeric derangement induced by anoxia/reoxygenation injury in NRVMs at sub-micromolar concentrations, and were more potent than CsA. Cardioprotection was observed also in adult mouse ventricular myocytes and human iPSc-derived cardiomyocytes, as well as ex vivo in perfused hearts. Thus, this study demonstrates that 63 and TR002 represent novel cardioprotective agents that inhibit PTP opening independent of CyPD targeting.

Emerging Risk Profile of Lung Cancer Therapy: Diffuse Alveolar Hemorrhage from Osimertinib.

Osimertinib is an oral epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used primarily in the treatment of metastatic non-small cell lung cancer. It is usually well tolerated with less than 5% of patients developing significant pulmonary toxicity from the medication, typically within the first few months after initiation. Previously reported pulmonary adverse reactions include pneumonitis (nonspecific interstitial pneumonia or other forms of acute interstitial process), fleeting asymptomatic infiltrates on imaging, and eosinophilic pneumonia. We present an interesting case of a 65-year-old female with recurrent metastatic adenocarcinoma of the lung, treated with Osimertinib for 4 months, who developed a previously unreported toxicity of diffuse alveolar hemorrhage (DAH) requiring mechanical ventilatory support.

Second-Generation Inhibitors of the Mitochondrial Permeability Transition Pore with Improved Plasma Stability.

Excessive mitochondrial matrix Ca2+ and oxidative stress leads to the opening of a high-conductance channel of the inner mitochondrial membrane referred to as the mitochondrial permeability transition pore (mtPTP). Because mtPTP opening can lead to cell death under diverse pathophysiological conditions, inhibitors of mtPTP are potential therapeutics for various human diseases. High throughput screening efforts led to the identification of a 3-carboxamide-5-phenol-isoxazole compounds as mtPTP inhibitors. While they showed nanomolar potency against mtPTP, they exhibited poor plasma stability, precluding their use in in vivo studies. Herein, we describe a series of structurally related analogues in which the core isoxazole was replaced with a triazole, which resulted in an improvement in plasma stability. These analogues were readily generated using the copper-catalyzed "click chemistry". One analogue, N-(5-chloro-2-methylphenyl)-1-(4-fluoro-3-hydroxyphenyl)-1H-1,2,3-triazole-4-carboxamide (TR001), was efficacious in a zebrafish model of muscular dystrophy that results from mtPTP dysfunction whereas the isoxazole isostere had minimal effect.

The Mitochondrial Permeability Transition in Mitochondrial Disorders.

Mitochondrial permeability transition pore (PTP), a (patho)physiological phenomenon discovered over 40 years ago, is still not completely understood. PTP activation results in a formation of a nonspecific channel within the inner mitochondrial membrane with an exclusion size of 1.5 kDa. PTP openings can be transient and are thought to serve a physiological role to allow quick Ca2+ release and/or metabolite exchange between mitochondrial matrix and cytosol or long-lasting openings that are associated with pathological conditions. While matrix Ca2+ and oxidative stress are crucial in its activation, the consequence of prolonged PTP opening is dissipation of the inner mitochondrial membrane potential, cessation of ATP synthesis, bioenergetic crisis, and cell death-a primary characteristic of mitochondrial disorders. PTP involvement in mitochondrial and cellular demise in a variety of disease paradigms has been long appreciated, yet the exact molecular entity of the PTP and the development of potent and specific PTP inhibitors remain areas of active investigation. In this review, we will (i) summarize recent advances made in elucidating the molecular nature of the PTP focusing on evidence pointing to mitochondrial FoF1-ATP synthase, (ii) summarize studies aimed at discovering novel PTP inhibitors, and (iii) review data supporting compromised PTP activity in specific mitochondrial diseases.

The unique histidine in OSCP subunit of F-ATP synthase mediates inhibition of the permeability transition pore by acidic pH.

The permeability transition pore (PTP) is a Ca2+-dependent mitochondrial channel whose opening causes a permeability increase in the inner membrane to ions and solutes. The most potent inhibitors are matrix protons, with channel block at pH 6.5. Inhibition is reversible, mediated by histidyl residue(s), and prevented by their carbethoxylation by diethylpyrocarbonate (DPC), but their assignment is unsolved. We show that PTP inhibition by H+ is mediated by the highly conserved histidyl residue (H112 in the human mature protein) of oligomycin sensitivity conferral protein (OSCP) subunit of mitochondrial F1FO (F)-ATP synthase, which we also show to undergo carbethoxylation after reaction of mitochondria with DPC. Mitochondrial PTP-dependent swelling cannot be inhibited by acidic pH in H112Q and H112Y OSCP mutants, and the corresponding megachannels (the electrophysiological counterpart of the PTP) are insensitive to inhibition by acidic pH in patch-clamp recordings of mitoplasts. Cells harboring the H112Q and H112Y mutations are sensitized to anoxic cell death at acidic pH. These results demonstrate that PTP channel formation and its inhibition by H+ are mediated by the F-ATP synthase.

Ca2+ binding to F-ATP synthase ß subunit triggers the mitochondrial permeability transition.

F-ATP synthases convert the electrochemical energy of the H+ gradient into the chemical energy of ATP with remarkable efficiency. Mitochondrial F-ATP synthases can also undergo a Ca2+-dependent transformation to form channels with properties matching those of the permeability transition pore (PTP), a key player in cell death. The Ca2+ binding site and the mechanism(s) through which Ca2+ can transform the energy-conserving enzyme into a dissipative structure promoting cell death remain unknown. Through in vitro, in vivo and in silico studies we (i) pinpoint the "Ca2+-trigger site" of the PTP to the catalytic site of the F-ATP synthase ß subunit and (ii) define a conformational change that propagates from the catalytic site through OSCP and the lateral stalk to the inner membrane. T163S mutants of the ß subunit, which show a selective decrease in Ca2+-ATP hydrolysis, confer resistance to Ca2+-induced, PTP-dependent death in cells and developing zebrafish embryos. These findings are a major advance in the molecular definition of the transition of F-ATP synthase to a channel and of its role in cell death.