Role of Lipids and Divalent Cations in Membrane Fusion Mediated by the Heptad Repeat Domain 1 of Mitofusin.

Mitochondria are highly dynamic organelles that constantly undergo fusion and fission events to maintain their shape, distribution and cellular function. Mitofusin 1 and 2 proteins are two dynamin-like GTPases involved in the fusion of outer mitochondrial membranes (OMM). Mitofusins are anchored to the OMM through their transmembrane domain and possess two heptad repeat domains (HR1 and HR2) in addition to their N-terminal GTPase domain. The HR1 domain was found to induce fusion via its amphipathic helix, which interacts with the lipid bilayer structure. The lipid composition of mitochondrial membranes can also impact fusion. However, the precise mode of action of lipids in mitochondrial fusion is not fully understood. In this study, we examined the role of the mitochondrial lipids phosphatidylethanolamine (PE), cardiolipin (CL) and phosphatidic acid (PA) in membrane fusion induced by the HR1 domain, both in the presence and absence of divalent cations (Ca2+ or Mg2+). Our results showed that PE, as well as PA in the presence of Ca2+, effectively stimulated HR1-mediated fusion, while CL had a slight inhibitory effect. By considering the biophysical properties of these lipids in the absence or presence of divalent cations, we inferred that the interplay between divalent cations and specific cone-shaped lipids creates regions with packing defects in the membrane, which provides a favorable environment for the amphipathic helix of HR1 to bind to the membrane and initiate fusion.

Higher stress response and altered quality of life in schizophrenia patients with low membrane levels of docosahexaenoic acid.

Schizophrenia is a severe, chronic, and heterogeneous mental disorder that affects approximately 1% of the world population. Ongoing research aims at clustering schizophrenia heterogeneity into various "biotypes" to identify subgroups of individuals displaying homogeneous symptoms, etiopathogenesis, prognosis, and treatment response. The present study is in line with this approach and focuses on a biotype partly characterized by a specific membrane lipid composition. We have examined clinical and biological data of patients with stabilized schizophrenia, including the fatty acid content of their erythrocyte membranes, in particular the omega-3 docosahexaenoic acid (DHA). Two groups of patients of similar size were identified: the DHA- group (N = 19) with a lower proportion of membrane DHA as compared to the norm in the general population, and the DHAn group (N = 18) with a normal proportion of DHA. Compared to DHAn, DHA- patients had a higher number of hospitalizations and a lower quality of life in terms of perceived health and physical health. They also exhibited significant higher interleukin-6 and cortisol blood levels. These results emphasize the importance of measuring membrane lipid and immunoinflammatory biomarkers in stabilized patients to identify a specific subgroup and optimize non-pharmacological interventions. It could also guide future research aimed at proposing specific pharmacological treatments.

An implicit and reliable neural measure quantifying impaired visual coding of facial expression: evidence from the 22q11.2 deletion syndrome.

Although various psychiatric disorders present with social-cognitive impairment, a measure assessing social-cognitive processes implicitly and reliably, with high selectivity and with enough signal-to-noise ratio (SNR) for individual evaluation of any population at any age, is lacking. Here we isolate a neural marker quantifying impaired visual coding of facial expression in individuals with 22q11.2 deletion syndrome (22q11DS) using frequency-tagging with electroencephalography (EEG). Twenty-two 22q11DS participants and 22 healthy controls were presented with changes of facial expression displayed at low, moderate, and high intensities every five cycles in a stream of one neutral face repeating 6 times per second (i.e., at a 6 Hz base rate). The brain response to expression changes tagged at the 1.2 Hz (i.e., 6 Hz/5) predefined frequency was isolated over occipito-temporal regions in both groups of participants for moderate- and high-intensity facial expressions. Neural sensitivity to facial expression was reduced by about 36% in 22q11DS, revealing impaired visual coding of emotional facial signals. The significance of the expression-change response was estimated for each single participant thanks to the high SNR of the approach. Further analyses revealed the high reliability of the response and its immunity from other neurocognitive skills. Interestingly, response magnitude was associated with the severity of positive symptoms, pointing to a potential endophenotype for psychosis risk. Overall, the present study reveals an objective, selective, reliable, and behavior-free signature of impaired visual coding of facial expression implicitly quantified from brain activity with high SNR. This novel tool opens avenues for clinical practice, providing a potential early biomarker for later psychosis onset and offering an alternative for individual assessment of social-cognitive functioning in even difficult-to-test participants.