OPA1 functions in mitochondria and dysfunctions in optic nerve

OPA1 is the major gene responsible for Dominant Optic Atrophy (DOA), a blinding disease that affects specifically the retinal ganglion cells (RGCs), which function consists in connecting the neuro-retina to the brain. OPA1 encodes an intra-mitochondrial dynamin, involved in inner membrane structures and ubiquitously expressed, raising the critical question of the origin of the disease pathophysiology. Here, we review the fundamental knowledge on OPA1 functions and regulations, highlighting their involvements in mitochondrial respiration, membrane dynamic and apoptosis. In light of these functions, we then describe the remarkable RGC mitochondrial network physiology and analyse data collected from animal models expressing OPA1 mutations. If, to date RGC mitochondria does not present any peculiarity at the molecular level, they represent possible targets of numerous assaults, like light, pressure, oxidative stress and energetic impairment, which jeopardize their function and survival, as observed in OPA1 mouse models. Although fascinating fields of investigation are still to be addressed on OPA1 functions and on DOA pathophysiology, we have reached a conspicuous state of knowledge with pertinent cell and animal models, from which therapeutic trials can be initiated and deeply evaluated

Chronic Eczematous Eruptions of the Elderly Are Associated with Chronic Exposure to Calcium Channel Blockers: Results from a Case–Control Study

It has been suggested that chronic eczematous eruptions of the elderly could be associated with chronic drug exposure. To determine the drugs associated with these eruptions, we conducted a case–control study on 102 cases and 204 controls. Cases were consecutive patients older than 60 years presenting with an eczematous eruption that had evolved continuously or recurrently for more than 3 months without a reliable cause. Two controls were matched to each case on age, sex, in/outpatient origin, and center. Information about drug exposure was obtained from patients and their pharmacists. Drug use for more than 3 months within the year preceding the eruption was compared between cases and controls. An association was found between calcium channel blockers (CCB) and eczema, with a matched OR (odds ratio) of 2.5 (95% CI (confidence interval): 1.3–4.6). To ascertain the course of patients after CCB withdrawal, two ancillary studies were performed on 74 patients with eczematous eruptions from our department before the case–control study period, and on 101 patients registered in the French “Pharmacovigilance” database. Healing of these eruptions after CCB withdrawal occurred in 83 and 68% of these cases, respectively. The long-term use of CCB is a risk factor for chronic eczematous eruptions of the elderly

Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells

A proteolytic cascade ensures that OMA1 cleaves and inactivates mitochondrial fusion protein OPA1 in times of stress, preventing damaged mitochondria from fusing with healthy organelles. (See also companion paper from Ehses et al. in this issue.

A modified self‐controlled case series method for event‐dependent exposures and high event‐related mortality, with application to COVID‐19 vaccine safety

We propose a modified self‐controlled case series (SCCS) method to handle both event‐dependent exposures and high event‐related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID‐19 vaccines. Event‐dependence of vaccinations, and high event‐related mortality, are likely to arise in other SCCS studies of COVID‐19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death

Roles of Probiotics and Prebiotics in Colon Cancer Prevention: Postulated Mechanisms and In-vivo Evidence

Probiotics are live bacteria that could exert health beneficial effects upon consumption. In additional to their conventional use as gut modulators, probiotics are investigated for their role to prevent cancer. In-vivo and molecular studies have demonstrated encouraging outcomes, mainly attributed to its antimicrobial effects against carcinogen-producing microorganisms, antimutagenic properties, and alteration of the tumor differentiation processes. Prebiotics are indigestible food components that could promote the growth of beneficial bacteria including probiotics. Present studies have suggested that prebiotics also possess protective effect against colon carcinogenesis, mainly attributed to the production of short chain fatty acids upon its fermentation by gut microflora, and alteration of gene-expressions in tumor cells. Synbiotic (combination of probiotic and prebiotic) has been found to exert a synergistic effect in improving colon carcinogenesis compared to when both were used individually. This paper highlights the colon cancer preventive effects by probiotics, prebiotics and synbiotics. In addition, the controversial outcomes on the insignificant effect of these food adjuncts will be discussed

Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1

m-AAA proteases cleave OPA1 to ensure a balance of long and short OPA1 isoforms, whereas cleavage by OMA1 causes an accumulation of the short OPA1 variants. (See also companion paper from Head et al. in this issue.

The Effect of OPA1 on Mitochondrial Ca2+ Signaling

The dynamin-related GTPase protein OPA1, localized in the intermembrane space and tethered to the inner membrane of mitochondria, participates in the fusion of these organelles. Its mutation is the most prevalent cause of Autosomal Dominant Optic Atrophy. OPA1 controls the diameter of the junctions between the boundary part of the inner membrane and the membrane of cristae and reduces the diffusibility of cytochrome c through these junctions. We postulated that if significant Ca2+ uptake into the matrix occurs from the lumen of the cristae, reduced expression of OPA1 would increase the access of Ca2+ to the transporters in the crista membrane and thus would enhance Ca2+ uptake. In intact H295R adrenocortical and HeLa cells cytosolic Ca2+ signals evoked with K+ and histamine, respectively, were transferred into the mitochondria. The rate and amplitude of mitochondrial [Ca2+] rise (followed with confocal laser scanning microscopy and FRET measurements with fluorescent wide-field microscopy) were increased after knockdown of OPA1, as compared with cells transfected with control RNA or mitofusin1 siRNA. Ca2+ uptake was enhanced despite reduced mitochondrial membrane potential. In permeabilized cells the rate of Ca2+ uptake by depolarized mitochondria was also increased in OPA1-silenced cells. The participation of Na+/Ca2+ and Ca2+/H+ antiporters in this transport process is indicated by pharmacological data. Altogether, our observations reveal the significance of OPA1 in the control of mitochondrial Ca2+ metabolism

Primary intestinal lymphangiectasia (Waldmann's disease)

Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. Prevalence is unknown. The main symptom is predominantly bilateral lower limb edema. Edema may be moderate to severe with anasarca and includes pleural effusion, pericarditis or chylous ascites. Fatigue, abdominal pain, weight loss, inability to gain weight, moderate diarrhea or fat-soluble vitamin deficiencies due to malabsorption may also be present. In some patients, limb lymphedema is associated with PIL and is difficult to distinguish lymphedema from edema. Exsudative enteropathy is confirmed by the elevated 24-h stool α1-antitrypsin clearance. Etiology remains unknown. Very rare familial cases of PIL have been reported. Diagnosis is confirmed by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Differential diagnosis includes constrictive pericarditis, intestinal lymphoma, Whipple's disease, Crohn's disease, intestinal tuberculosis, sarcoidosis or systemic sclerosis. Several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum) or with extra-intestinal localizations were reported in PIL patients. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with its ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and avoid lacteal overloading. Other inconsistently effective treatments have been proposed for PIL patients, such as antiplasmin, octreotide or corticosteroids. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. PIL outcome may be severe even life-threatening when malignant complications or serous effusion(s) occur