AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer's disease.

Microglia-driven neuroinflammation plays an important role in the development of Alzheimer's disease. Microglia activation is accompanied by the formation and chronic expression of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aß) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp-/- APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased reactive oxygen species and the dilated endoplasmic reticulum. The size and number of Aß plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp-/-APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in Alzheimer's disease associated oxidative stress and neurodegeneration.

Human rod photoreceptor outer segments are supported by accessory inner segment structures.

The first steps in vision take place in photoreceptor cells, which are highly compartmentalized neurons exhibiting significant structural variation across species. The light-sensitive ciliary compartment, called the outer segment, is located atop of the cell soma, called the inner segment. In this study, we present an ultrastructural analysis of human photoreceptors, which reveals that, in contrast to this classic arrangement, the inner segment of human rods extends alongside the outer segment to form a structure hereby termed the "accessory inner segment". While reminiscent of the actin-based microvilli known as "calyceal processes" observed in other species, the accessory inner segment is a unique structure: (1) it contains an extensive microtubule-based cytoskeleton, (2) it extends far alongside the outer segment, (3) its diameter is comparable to that of the outer segment, (4) it contains numerous mitochondria, and (5) it forms electron-dense structures that likely mediate adhesion to the outer segment. Given that the spacing of extrafoveal human photoreceptors is more sparse than in non-primate species, with vast amounts of interphotoreceptor matrix present between cells, the closely apposed accessory inner segment likely provides structural support to the outer segment. This discovery expands our understanding of the human retina and directs future studies of human photoreceptor function in health and disease.

Poor sleep quality is associated with decreased regional brain glucose metabolism in healthy middle-aged adults.

Sleep disturbance is associated with the development of neurodegenerative disease. We aimed to address the effects of sleep quality on brain glucose metabolism measured by 18F-Fl uorodeoxyglucose (18F-FDG) positron emission tomography (PET) in healthy middle-aged adults. A total of 378 healthy men (mean age: 42.8±3.6 years) were included in this study. Participants underwent brain 18F-FDG PET and completed the Korean version of the Pittsburgh Sleep Quality Index (PSQI-K). Additionally, anthropometric measurements were obtained. PETs were spatially normalized to MNI space using PET templates from SPM5 with PMOD. The Automated Anatomical Labeling 2 atlas was used to define regions of interest (ROIs). The mean uptake of each ROI was scaled to the mean of the global cortical uptake of each individual and defined as the standardized uptake value ratio (SUVR). After the logarithmic transformation of the regional SUVR, the effects of the PSQI-K on the regional SUVR were investigated using Bayesian hierarchical modeling. Brain glucose metabolism of the posterior cingulate, precuneus, and thalamus showed a negative association with total PSQI-K scores in the Bayesian model ROI-based analysis. Voxel-based analysis using statistical parametric mapping revealed a negative association between the total PSQI-K scores and brain glucose metabolism of the precuneus, postcentral gyrus, posterior cingulate, and thalamus. Poor sleep quality is negatively associated with brain glucose metabolism in the precuneus, posterior cingulate, and thalamus. Therefore, the importance of sleep should not be overlooked, even in healthy middle-aged adults.

Clinical assessment and striatal dopaminergic activity in healthy controls and patients with Parkinson's disease: a Bayesian approach.

OBJECTIVES: We aimed to evaluate correlations between striatal dopamine transporter (DAT) uptake and clinical assessments in both patients with Parkinson's disease (PD) and healthy controls. METHODS: This study enrolled 193 healthy controls, and 581 patients with PD. They underwent various clinical assessments and 123I-FP-CIT SPECT scans. After reconstruction, attenuation correction, and normalization of SPECT images, counts were measured from the bilateral caudate and putamen, and the occipital cortex for reference. Count densities for each region were extracted and used to calculate striatal binding ratios (SBRs) for each striatal region. SBR is calculated as (target region/reference region)-1. After logarithmic transformation of striatal SBRs, we analyzed the effects of clinical assessments on striatal SBRs using Bayesian hierarchical modeling. RESULTS: MDS-UPDRS total score, part I, part II, part III, Epworth Sleepiness Scale, REM sleep behavior disorder screening questionnaire, SCOPA-AUT total score were negatively associated with striatal SBR in patients with PD. Also, HVLT recognition discrimination was positively associated with striatal SBR in both healthy controls and patients with PD. In healthy control, MDS-UPDRS part II, MOCA, SCOPA-AUT total score were positively associated with striatal SBR. CONCLUSION: We demonstrated that motor symptom, sleep disturbance, autonomic symptom, and cognition of patients with PD were associated with striatal dopaminergic activity. In healthy controls, motor symptoms, autonomic symptom, and cognition were associated with striatal dopaminergic activity, some of which showing the opposite direction with patients with PD. This result might provide new insight to underlying mechanism of dopamine system with motor and non-motor assessments.

Scalable electron tomography for connectomics.

We demonstrate limited-tilt, serial section electron tomography (ET), which can non-destructively map brain circuits over large 3D volumes and reveal high-resolution, supramolecular details within subvolumes of interest. We show accelerated ET imaging of thick sections (>500 nm) with the capacity to resolve key features of neuronal circuits including chemical synapses, endocytic structures, and gap junctions. Furthermore, we systematically assessed how imaging parameters affect image quality and speed to enable connectomic-scale projects.

Administration of Bicarbonate Protects Mitochondria, Rescues Retinal Ganglion Cells, and Ameliorates Visual Dysfunction Caused by Oxidative Stress.

Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is a key regulator of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, which is known to protect mitochondria and promote RGC survival. However, the precise molecular mechanisms connecting the sAC-mediated signaling pathway with mitochondrial protection in RGCs against oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress induced by ischemic injury and paraquat administration, we found that administration of bicarbonate, as an activator of sAC, protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death. Notably, the administration of bicarbonate ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.

Efficacy of Empirical 131 I Radioiodine Therapy in Well-Differentiated Thyroid Carcinoma Patients With Thyroglobulin-Elevated Negative Iodine Scintigraphy Syndrome : A Systematic Review and Meta-analysis.

OBJECTIVES: This study aimed to perform a systematic review and meta-analysis on the efficacy of empirical high-dose radioiodine therapy in treating differentiated thyroid cancer patients with thyroglobulin (Tg)-elevated negative iodine scintigraphy (TENIS) syndrome. METHODS: We searched PubMed, EMBASE, and the Cochrane Library to identify relevant studies published until April 2022. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and registered in an international prospective register of systematic reviews (PROSPERO). Meta-analyses of proportions and odds ratios were performed to assess the beneficial effect of empirical high-dose radioiodine therapy in patients with TENIS syndrome. Subgroup analysis was also performed according to the presence of micrometastasis or macrometastasis. RESULTS: We identified 14 studies including 690 patients who received empirical high-dose radioiodine therapy for TENIS syndrome. Those who had micrometastasis exhibited additional lesions not previously observed on diagnostic whole-body scan (prop = 0.64, 95% confidence interval [CI], 0.51-0.77) and had reduced serum Tg levels (prop = 0.69; 95% CI, 0.52-0.84) after empirical radioiodine treatment. No such findings were observed among patients with macrometastasis. Moreover, we found that the empirical radioiodine treatment group had lower serum Tg levels than did controls (odds ratio = 0.27; 95% CI, 0.09-0.87), which suggests a lower risk of disease progression. CONCLUSIONS: Our findings indicate that empirical high-dose radioiodine therapy promoted beneficial effects and could be recommended for patients with TENIS syndrome, especially those with micrometastasis.

Development of examination objectives for the Korean paramedic and emergency medical technician examination: a survey study.

PURPOSE: The duties of paramedics and emergency medical technicians (P&EMTs) are continuously changing due to developments in medical systems. This study presents evaluation goals for P&EMTs by analyzing their work, especially the tasks that new P&EMTs (with less than 3 years' experience) find difficult, to foster the training of P&EMTs who could adapt to emergency situations after graduation. METHODS: A questionnaire was created based on prior job analyses of P&EMTs. The survey questions were reviewed through focus group interviews, from which 253 task elements were derived. A survey was conducted from July 10, 2023 to October 13, 2023 on the frequency, importance, and difficulty of the 6 occupations in which P&EMTs were employed. RESULTS: The P&EMTs' most common tasks involved obtaining patients' medical histories and measuring vital signs, whereas the most important task was cardiopulmonary resuscitation (CPR). The task elements that the P&EMTs found most difficult were newborn delivery and infant CPR. New paramedics reported that treating patients with fractures, poisoning, and childhood fever was difficult, while new EMTs reported that they had difficulty keeping diaries, managing ambulances, and controlling infection. CONCLUSION: Communication was the most important item for P&EMTs, whereas CPR was the most important skill. It is important for P&EMTs to have knowledge of all tasks; however, they also need to master frequently performed tasks and those that pose difficulties in the field. By deriving goals for evaluating P&EMTs, changes could be made to their education, thereby making it possible to train more capable P&EMTs.

Mesoscale Metabolic Channeling Revealed by Multimodal Microscopy.

Metabolic homeostasis within cells and tissues requires engagement of catabolic and anabolic pathways consuming nutrients needed to generate energy to drive these and other subcellular processes. However, the current understanding of cell homeostasis and metabolism, including how cells utilize nutrients, comes largely from tissue and cell models analyzed after fractionation. These bulk strategies do not reveal the spatial characteristics of cell metabolism at the single cell level, and how these aspects relate to the location of cells and organelles within the complexity of the tissue they reside within. Here we pioneer the use of high-resolution electron and stable isotope microscopy (MIMS-EM) to quantitatively map the fate of nutrient-derived 13C atoms at subcellular scale. When combined with machine-learning image segmentation, our approach allows us to establish the cellular and organellar spatial pattern of glucose 13C flux in hepatocytes in situ. We applied network analysis algorithms to chart the landscape of organelle-organelle contact networks and identified subpopulations of mitochondria and lipid droplets that have distinct organelle interactions and 13C enrichment levels. In addition, we revealed a new relationship between the initiation of glycogenesis and proximity of lipid droplets. Our results establish MIMS-EM as a new tool for tracking and quantifying nutrient metabolism at the subcellular scale, and to identify the spatial channeling of nutrient-derived atoms in the context of organelle-organelle interactions in situ.

AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer's disease.

Microglia-driven neuroinflammation plays an important role in the development of Alzheimer's disease (AD). Microglia activation is accompanied by the formation and chronic maintenance of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aß) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp-/- APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased ROS and the dilated ER. The size and number of Aß plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp-/- APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in AD associated oxidative stress and neurodegeneration.

Activating soluble adenylyl cyclase protects mitochondria, rescues retinal ganglion cells, and ameliorates visual dysfunction caused by oxidative stress.

Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is one of the key regulators of the cAMP/PKA signaling pathway. However, the precise molecular mechanisms underlying the sAC-mediated signaling pathway and mitochondrial protection in RGCs that counter oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress, we found that activating sAC protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death in a paraquat oxidative stress model. Notably, sAC activation ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.

New rabies viral resources for multi-scale neural circuit mapping.

Comparisons and linkage between multiple imaging scales are essential for neural circuit connectomics. Here, we report 20 new recombinant rabies virus (RV) vectors that we have developed for multi-scale and multi-modal neural circuit mapping tools. Our new RV tools for mesoscale imaging express a range of improved fluorescent proteins. Further refinements target specific neuronal subcellular locations of interest. We demonstrate the discovery power of these new tools including the detection of detailed microstructural changes of rabies-labeled neurons in aging and Alzheimer's disease mouse models, live imaging of neuronal activities using calcium indicators, and automated measurement of infected neurons. RVs that encode GFP and ferritin as electron microscopy (EM) and fluorescence microscopy reporters are used for dual EM and mesoscale imaging. These new viral variants significantly expand the scale and power of rabies virus-mediated neural labeling and circuit mapping across multiple imaging scales in health and disease.

Comparative Study of Different Imaging Modalities for Diagnosis of Bone Metastases of Prostate Cancer: A Bayesian Network Meta-analysis.

PURPOSE: This study aimed to compare the diagnostic performances of 8 different imaging modalities for preoperative detection of bone metastases in prostate cancer patients by performing a network meta-analysis using direct comparison studies with 2 or more imaging techniques. PATIENTS AND METHODS: We searched PubMed, Embase, and Cochrane Library for studies evaluating the performances of 8 different imaging modalities for the preoperative detection of bone metastases in prostate cancer patients. The network meta-analysis was performed in patient-based analysis. The consistency was evaluated by examining the agreement between direct and indirect treatment effects, and the surface under the cumulative ranking curve (SUCRA) values were obtained to calculate the probability of each imaging modality being the most effective diagnostic method. RESULTS: A total of 999 patients from 13 direct comparison studies using 8 different imaging modalities for preoperative detection or follow-up of bone metastases in prostate cancer patients were included. For the detection of bone metastases of prostate cancer, 68 Ga-PSMA-11 PET/CT showed the highest SUCRA values of sensitivity, positive predictive value, accuracy, and diagnostic odds ratio. In addition, 18 F-NaF PET/CT and SPECT/CT showed high SUCRA values. CONCLUSIONS: 68 Ga-PSMA-11 PET/CT showed the highest SUCRA values. Other imaging modalities showed complementary diagnostic roles for preoperative detection of bone metastases in patients with prostate cancer, except bone scintigraphy and MRI.

Polyhexamethylene Guanidine Phosphate Enhanced Procoagulant Activity through Oxidative-Stress-Mediated Phosphatidylserine Exposure in Platelets.

Polyhexamethylene guanidine phosphate (PHMG-p) is a common biocidal disinfectant that is widely used in industry and household products. However, PHMG-p was misused as a humidifier disinfectant (HD) in South Korea, which had fatal health effects. Various health problems including cardiovascular diseases were observed in HD-exposed groups. However, the potential underlying mechanism of HD-associated cardiovascular diseases is poorly understood. Here, we examined the procoagulant activity of platelets caused by PHMG-p and clarified the underlying mechanism. PHMG-p enhanced phosphatidylserine (PS) exposure through alteration of phospholipid transporters, scramblase, and flippase. Intracellular calcium elevation, intracellular ATP depletion, and caspase-3 activation appeared to underlie phospholipid transporter dysregulation caused by PHMG-p, which was mediated by oxidative stress and mitochondrial dysfunction. Notably, antioxidant enzyme catalase and calcium chelator EGTA reversed PHMG-p-induced PS exposure and thrombin generation, confirming the contributive role of oxidative stress and intracellular calcium in the procoagulant effects of PHMG-p. These series of events led to procoagulant activation of platelets, which was revealed as enhanced thrombin generation. Collectively, PHMG-p triggered procoagulant activation of platelets, which may promote prothrombotic risks and cardiovascular diseases. These findings improve our understanding of HD-associated cardiovascular diseases.

AIBP: A New Safeguard against Glaucomatous Neuroinflammation.

Glaucoma is a group of ocular diseases that cause irreversible blindness. It is characterized by multifactorial degeneration of the optic nerve axons and retinal ganglion cells (RGCs), resulting in the loss of vision. Major components of glaucoma pathogenesis include glia-driven neuroinflammation and impairment of mitochondrial dynamics and bioenergetics, leading to retinal neurodegeneration. In this review article, we summarize current evidence for the emerging role of apolipoprotein A-I binding protein (AIBP) as an important anti-inflammatory and neuroprotective factor in the retina. Due to its association with toll-like receptor 4 (TLR4), extracellular AIBP selectively removes excess cholesterol from the plasma membrane of inflammatory and activated cells. This results in the reduced expression of TLR4-associated, cholesterol-rich lipid rafts and the inhibition of downstream inflammatory signaling. Intracellular AIBP is localized to mitochondria and modulates mitophagy through the ubiquitination of mitofusins 1 and 2. Importantly, elevated intraocular pressure induces AIBP deficiency in mouse models and in human glaucomatous retina. AIBP deficiency leads to the activation of TLR4 in Müller glia, triggering mitochondrial dysfunction in both RGCs and Müller glia, and compromising visual function in a mouse model. Conversely, restoring AIBP expression in the retina reduces neuroinflammation, prevents RGCs death, and protects visual function. These results provide new insight into the mechanism of AIBP function in the retina and suggest a therapeutic potential for restoring retinal AIBP expression in the treatment of glaucoma.

Comparison of Recombinant Human Thyroid-Stimulating Hormone and Thyroid Hormone Withdrawal for 131 I Therapy in Patients With Intermediate- to High-Risk Thyroid Cancer : A Systematic Review and Meta-analysis.

BACKGROUND: This meta-analysis and systematic review aimed to evaluate the therapeutic efficacy and advantages associated with the use of recombinant human thyroid-stimulating hormone (rhTSH) for radioactive iodine (RAI) therapy in patients with intermediate- to high-risk differentiated thyroid cancer. PATIENTS AND METHODS: MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles reporting clinical outcomes of rhTSH compared with thyroid hormone withdrawal (THW) in patients with intermediate- to high-risk differentiated thyroid cancer published between January 2012 and June 2023. Meta-analyses were performed (PROSPERO registration number: CRD42022340915) to assess the success rate of radioiodine remnant ablation (RRA) in patients with intermediate to high risk and determine the disease control rate among patients with distant metastases, evaluated using the RECIST criteria. RESULTS: Thirteen studies involving 1858 patients were included in the meta-analysis. Pooled analyses revealed significantly higher overall RRA success rate in the rhTSH group compared with the THW group, with a risk ratio (RR) of 1.12 (95% confidence interval [CI], 1.01-1.25). However, in the subgroup analysis of high-risk patients, pooled analyses showed no significant differences in RRA success rate between the rhTSH group compared with the THW group with a pooled RR of 1.05 (95% CI, 0.88-1.24). In patients with distant metastases, there were no significant differences in the disease control rate between groups, with a pooled RR of 1.06 (95% CI, 0.78-1.44). CONCLUSIONS: rhTSH for RAI therapy is a practical option for RAI therapy in patients with intermediate- to high-risk thyroid cancer, including those with distant metastases.

Clinical Implications of Adding SPECT/CT to Radioiodine Whole-Body Scan in Patients With Differentiated Thyroid Cancer: A Systematic Review and Meta-analysis.

PURPOSE: This study aimed to determine the usefulness of adding SPECT/CT to radioiodine whole-body scans (WBSs) for the treatment of differentiated thyroid cancer (DTC). PATIENTS AND METHODS: A systematic review and meta-analysis were performed following the PRISMA guidelines (PROSPERO registration: CRD42022341732) to compare the feasibility of conclusive readings and the frequency of changes in treatment plans in patients with DTC undergoing WBS + SPECT/CT versus WBS. MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles concerning thyroid cancer, radioactive iodine, and SPECT/CT or SPECT, published before August 16, 2023. Studies not comparing WBS + SPECT/CT with WBS, those lacking target outcomes, and those not involving human subjects were excluded. The risk of bias was assessed using the RoBANS 2.0 (Risk of Bias Assessment Tool for Nonrandomized Studies) tool. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system was used to evaluate the quality of evidence and strength of recommendations. RESULTS: A total of 30 studies (prospective n = 9, retrospective n = 21) were included in the meta-analyses. Adding SPECT/CT to WBS was shown to increase conclusive readings for cervical lesions, extracervical lesions, and all regions. Lesion-based analyses showed improvements of 14%, 20%, and 18%, respectively, whereas scan-based analyses showed improvements of 27%, 9%, and 34%. The addition of SPECT/CT to WBS led to changes in 30% of treatment plans after diagnostic scans and 9% of treatment plans after posttherapeutic scans. The quality of evidence and strength of recommendations were low. CONCLUSIONS: Compelling evidence demonstrates that the addition of SPECT/CT to WBS improves lesion localization, diagnostic performance, and therapy plan for patients with DTC.

Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.

Cristae are high-curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous lipid-based mechanisms have yet to be elucidated. Here, we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the inner mitochondrial membrane against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. This model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that cardiolipin is essential in low-oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of cardiolipin is dependent on the surrounding lipid and protein components of the IMM.