Wen Han Tong

Leucine is a central nutrient signal and a ketogenic amino acid that fuels metabolism, yet how it is imported into mitochondria remains incompletely defined. Sideroflexins are conserved inner mitochondrial membrane proteins implicated in amino acid transport, but their mechanism and substrate specificity remain unclear. Using cryogenic electron microscopy, we determined the structure of SFXN1 in its matrix-open conformation. AlphaFold and Boltz co-folding of SFXN1 with a library of human metabolites identified leucine as a candidate substrate, findings supported by thermal stability measurements and mitochondrial transport assays. Comparison with a cytoplasmic-open-model reveals an alternating-access toggle-switch mechanism of transport. Together, these findings uncover the molecular basis of leucine transport by SFXN1 and provide a framework for understanding its role in metabolism and disease.

Alzheimer's disease (AD) is a degenerative brain disorder with a long prodromal period. An APPNL-G-F knock-in mouse model is a preclinical model to study incipient pathologies during the early stages of AD. Despite behavioral tests revealing broad cognitive deficits in APPNL-G-F mice, detecting these impairments at the early disease phase has been challenging. In a cognitively demanding task that assessed episodic-like memory, 3-month-old wild-type mice could incidentally form and retrieve ‘what–where–when’ episodic associations of their past encounters. However, 3-month-old APPNL-G-F mice, corresponding to an early disease stage without prominent amyloid plaque pathology, displayed impairment in recalling ‘what–where’ information of past episodes. Episodic-like memory is also sensitive to the effect of age. Eight-month-old wild-type mice failed to retrieve conjunctive ‘what–where–when’ memories. This deficit was also observed in 8-month-old APPNL-G-F mice. c-Fos expression revealed that impaired memory retrieval in APPNL-G-F mice was accompanied by abnormal neuronal hyperactivity in the medial prefrontal cortex and CA1 dorsal hippocampus. These observations can be used for risk stratification during preclinical AD to detect and delay the progression into dementia.

Arginine vasopressin (AVP) is expressed in both hypothalamic and extra-hypothalamic neurons. The expression and role of AVP exhibit remarkable divergence between these two neuronal populations. Polysynaptic pathways enable these neuronal groups to regulate each other. AVP neurons in the paraventricular nucleus of the hypothalamus increase the production of adrenal stress hormones by stimulating the hypothalamic–pituitary–adrenal axis. Outside the hypothalamus, the medial amygdala also contains robust amounts of AVP. Contrary to the hypothalamic counterpart, the expression of extra-hypothalamic medial amygdala AVP is sexually dimorphic, in that it is preferentially transcribed in males in response to the continual presence of testosterone. Male gonadal hormones typically generate a negative feedback on the neuroendocrine stress axis. Here, we investigated whether testosterone-responsive medial amygdala AVP neurons provide negative feedback to hypothalamic AVP, thereby providing a feedback loop to suppress stress endocrine response during periods of high testosterone secretion. Contrary to our expectation, we found that AVP overexpression within the posterodorsal medial amygdala increased the recruitment of hypothalamic AVP neurons during stress, without affecting the total number of AVP neurons or the number of recently activated neurons following stress. These observations suggest that the effects of testosterone on extra-hypothalamic AVP facilitate stress responsiveness through permissive influence on the recruitment of hypothalamic AVP neurons.

Toxoplasma gondii is a protozoan parasite with a complex life cycle and a cosmopolitan host range. The asexual part of its life cycle can be perpetually sustained in a variety of intermediate hosts through a combination of carnivory and vertical transmission. However, T. gondii produces gametes only in felids after the predation of infected intermediate hosts. The parasite changes the behavior of its intermediate hosts by reducing their innate fear to cat odors and thereby plausibly increasing the probability that the definitive host will devour the infected host. Here, we provide a short description of such parasitic behavioral manipulation in laboratory rodents infected with T. gondii, along with a bird’s eye view of underpinning biological changes in the host. We also summarize critical gaps and opportunities for future research in this exciting research area with broad implications in the transdisciplinary study of host–parasite relationships. Graphical abstract