Biochemistry seminars

Thesis presentation by Tiffany Zhang, graduate fellow in the Vinogradova Lab at The Rockefeller University, on chemical proteomics approaches revealing post-translational remodeling of endosomal pathways during macrophage activation. Open to the tri-institutional community.

Different brain cell types exhibit distinct metabolic signatures that link energy economy to cellular function. Astrocytes and neurons, for instance, diverge dramatically in their reliance on glycolysis versus oxidative phosphorylation, underscoring that metabolic fuel efficiency is not uniform across cell types. A key factor shaping this divergence is the structural organization of the mitochondrial respiratory chain into supercomplexes. Specifically, complexes I (CI) and III (CIII) form a CI–CIII supercomplex, but the degree of this assembly varies by cell type. In neurons, CI is predominantly integrated into supercomplexes, resulting in highly efficient mitochondrial respiration and minimal reactive oxygen species (ROS) generation. Conversely, in astrocytes, a larger fraction of CI remains unassembled, freely existing apart from CIII, leading to reduced respiratory efficiency and elevated mitochondrial ROS production. Despite this apparent inefficiency, astrocytes boast a highly adaptable metabolism capable of responding to diverse stressors. Their looser CI–CIII organization allows for flexible ROS signaling, which activates antioxidant programs via transcription factors like Nrf2. This modular architecture enables astrocytes not only to balance energy production but also to support neuronal health and influence complex organismal behaviors.

Astrocytes release glutamate by regulated exocytosis in health and disease Vladimir Parpura, International Translational Neuroscience Research Institute, Zhejiang Chinese Medical University, Hangzhou, P.R. China Parpura will present you with the evidence that astrocytes, a subtype of glial cells in the brain, can exocytotically release the neurotransmitter glutamate and how this release is regulated. Spatiotemporal characteristic of vesicular fusion that underlie glutamate release in astrocytes will be discussed. He will also present data on a translational project in which this release pathway can be targeted for the treatment of glioblastoma, the deadliest brain cancer.

Do You Know Your Blood Glucose Level? You Probably Should! A single measurement is not enough to truly understand your metabolic health. Blood glucose levels fluctuate dynamically, and meaningful insights require continuous monitoring over time. But glucose is just one example. Many other molecular concentrations in the body are not static. Their variations are influenced by individual physiology and overall health. PhenoSign, a Swiss MedTech startup, is on a mission to become the leader in real-time molecular analysis of complex fluids, supporting clinical decision-making and life sciences applications. By providing real-time, in-situ molecular insights, we aim to advance medicine and transform life sciences research. This talk will provide an overview of PhenoSign’s journey since its inception in 2022—our achievements, challenges, and the strategic roadmap we are executing to shape the future of real-time molecular diagnostics.

My laboratory has made an intriguing discovery that mitochondrial stress in one tissue can be communicated to distal tissues. We find that mitochondrial stress in the nervous system triggers the production of entities known as mitokines. These mitokines are discharged from the nervous system, orchestrating a response in peripheral tissues that extends the lifespan of C. elegans. The revelation came as a surprise, given the prevalent belief that cell autonomous mechanisms would underlie the relationship between mitochondrial function and aging. It was also surprising given the prevailing dogma that mitochondrial function must be increased, not decreased, to improve health and longevity. Our work also underscores the fact that mitochondria, which originated as a microbial entity and later evolved into an intracellular symbiont, have retained their capacity for intercommunication, now facilitated by signals from the nervous system. We hypothesize that this communication has evolved as a mechanism to reduce infection from pathogens.

Parvalbumin-positive GABAergic interneurons (PV-INs) provide inhibitory control of excitatory neuron activity, coordinate circuit function, and regulate behavior and cognition. PV-INs are uniquely susceptible to loss and dysfunction in traumatic brain injury (TBI) and epilepsy but the cause of this susceptibility is unknown. One hypothesis is that PV-INs use specialized metabolic systems to support their high-frequency action potential firing and that metabolic stress disrupts these systems, leading to their dysfunction and loss. Metabolism-based therapies can restore PV-IN function after injury in preclinical TBI models. Based on these findings, we hypothesize that (1) PV-INs are highly metabolically specialized, (2) these specializations are lost after TBI, and (3) restoring PV-IN metabolic specializations can improve PV-IN function as well as TBI-related outcomes. Using novel single-cell approaches, we can now quantify cell-type-specific metabolism in complex tissues to determine whether PV-IN metabolic dysfunction contributes to the pathophysiology of TBI.

The basis of the mind, of mental states, and complex behaviors is the flow of energy through microscopic and macroscopic brain structures. Energy flow through brain circuits is powered by thousands of mitochondria populating the inside of every neuron, glial, and other nucleated cell across the brain-body unit. This seminar will cover emerging approaches to study the mind-mitochondria connection and present early attempts to map the distribution and diversity of mitochondria across brain tissue. In rodents, I will present convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct behaviorally-relevant mitochondrial phenotypes exist across large-scale mouse brain networks. Extending these findings to the human brain, I will present a developing systematic biochemical and molecular map of mitochondrial variation across cortical and subcortical brain structures, representing a foundation to understand the origin of complex energy patterns that give rise to the human mind.

Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Motivated by the identification of autism-associated mutations in SLC7A5, a transporter for metabolically essential large neutral amino acids (LNAAs), we utilized metabolomic profiling to investigate the metabolic states of the cerebral cortex across various developmental stages. Our findings reveal significant metabolic restructuring occurring in the forebrain throughout development, with specific groups of metabolites exhibiting stage-specific changes. Through the manipulation of Slc7a5 expression in neural cells, we discovered an interconnected relationship between the metabolism of LNAAs and lipids within the cortex. Neuronal deletion of Slc7a5 influences the postnatal metabolic state, resulting in a shift in lipid metabolism and a cell-type-specific modification in neuronal activity patterns. This ultimately gives rise to enduring circuit dysfunction.

Humans and other animals evolved in habitats fraught with a range of environmental challenges to their bodies and brains. Accordingly, cells and organ systems possess adaptive stress-responsive signaling pathways that enable them to not only withstand environmental challenges, but also to prepare for future challenges and function more efficiently. These phylogenetically conserved processes are the foundation of the hormesis principle in which repeated exposures to low to moderate amounts of an environmental challenge improve cellular and organismal fitness. Here I describe cellular and molecular mechanisms by which cells in the brain and body respond to intermittent fasting and exercise in ways that enhance performance and counteract aging and disease processes. Switching back and forth between adaptive stress response (during fasting and exercise) and growth and plasticity (eating, resting, sleeping) modes enhances the performance and resilience of various organ systems. While pharmacological interventions that engage a particular hormetic mechanism are being developed, it seems unlikely that any will prove superior to fasting and exercise.