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Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I 2 +III 2 , resolved at 3.7 Å by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1 DEL:E258-D260 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Amygdala activation by emotional arousal during memory formation can prioritize events for long-term memory. Building upon our prior demonstration that brief electrical stimulation to the human amygdala reliably improved long-term recognition memory for images of neutral objects without eliciting an emotional response, our study aims to explore and describe individual differences and stimulation-related factors in amygdala-mediated memory modulation. Thirty-one patients undergoing intracranial monitoring for intractable epilepsy were shown neutral object images paired with direct amygdala stimulation during encoding with recognition memory tested immediately and one day later. Adding to our prior sample, we found an overall memory enhancement effect without subjective emotional arousal at the one-day delay, but not at the immediate delay, for previously stimulated objects compared to not stimulated objects. Importantly, we observed a larger variation in performance across this larger sample than our initial sample, including some participants who showed a memory impairment for stimulated objects. Of the explored individual differences, the factor that most accounted for variability in memory modulation was each participant's pre-operative memory performance. Worse memory performance on standardized neuropsychological tests was associated with a stronger susceptibility to memory modulation in a positive or negative direction. Sex differences and the frequency of interictal epileptiform discharges (IEDs) during testing also accounted for some variance in amygdala-mediated memory modulation. Given the potential and challenges of this memory modulation approach, we discuss additional individual and stimulation factors that we hope will differentiate between memory enhancement and impairment to further optimize the potential of amygdala-mediated memory enhancement for therapeutic interventions., Competing Interests: Declarations. Ethics approval: This study was approved by the Emory University Institutional Review Board (IRB). Consent to participate: Prior to participating in the study, all volunteers received and signed a written informed consent that was approved by the Emory University IRB. Consent for publication: All authors consented to this publication. Conflicts of interest/Competing interests: None of the authors declared conflicts of interest., (© 2024. The Psychonomic Society, Inc.)

Objective: The current study sought to characterize the relationship of the N400 (N4) effect event-related potential to Alzheimer's disease (AD) biomarkers and broader cognition in older adults on the late-life cognitive continuum., Method: Participants who were cognitively intact (n = 43), or had amnestic mild cognitive impairment (MCI; n = 19), or mild AD (n = 12), completed a word-pair judgement task during concurrent EEG recording to elicit the N400. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and biomarker data (PET-imaged beta-amyloid (aβ) deposition, apolipoprotein-E ε4 (APOE4) allele status, hippocampal volumes) were collected as part of a larger study., Results: The AD group had slower response times and poorer accuracy on the word-pair judgement task than the intact group. The N4 effect was smaller and occurred later in AD relative to intact participants. MCI participants' values were intermediate. N4 effect amplitudes were not associated with RBANS scores but were positively associated with aβ deposition. Conversely, poorer performance across most RBANS Indexes and the Total score was associated with longer N4 latencies. There was also a negative association between hippocampal volumes and the N4 latency and a positive association between aβ deposition and latency. Finally, the latency of the N4 independently predicted variance in RBANS Total scores, above and beyond aβ deposition, hippocampal volumes, and APOE4 allele status., Conclusions: These findings support the relevance of the N4 effect in individuals along the late-life cognitive continuum, and motivate future studies into its potential as a longitudinal predictor in AD., (Copyright © 2024 Elsevier B.V. All rights reserved.)