Mitochondrial Heterogeneity in hippocampal CA1 and granular dentate gyrus neurons

• Applicant: Almudena del Río Martín, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553397020

This proposal aims to elucidate mitochondrial diversity and its implications for the coupling of mitochondrial bioenergetics and neuronal function between different classes of hippocampal principal neurons, focusing on the dentate gyrus (DG) and CA1 regions. Neurons, due to differences in size, firing frequency, myelination patterns, or neurotransmitter use, exhibit great heterogeneity in energy demands, which is reflected in their mitochondrial content, morphology, and functionality. Changes in mitochondrial mass and morphology occur by a process known as mitochondrial dynamics, in which these organelles fuse or fission in response to specific bioenergetic needs or other adaptations in mitochondrial function, such as in calcium (Ca2+) buffering, which regulates important neuronal electrophysiological parameters, including neurotransmission and excitability. However, the exact links between the heterogeneity of mitochondrial morphologies and neuronal functionality is poorly understood. In my study, I will focus on the hippocampus, specifically CA1 and DG excitatory projection neurons, which have been reported to exhibit remarkably distinct mitochondrial morphologies, e.g., when comparing dendritic vs. axonal mitochondria. Moreover, CA1 and DG neurons also exhibit differential mRNA expression levels of mitochondrial genes, including for key pathways such as the mitochondrial calcium uniporter (MCU) complex, a main entry pathway of Ca2+ from the cytoplasm to the mitochondrial matrix, which regulates bioenergetics but at the same time cytosolic Ca2+ levels. This suggests profound heterogeneity in mitochondrial functions between the two neuron classes. In this study, I will combine advanced imaging with cellular and molecular techniques to systematically compare the mitochondrial morphologies and dynamics, as well as the underlying mitochondrial proteomes and the resulting bioenergetic and Ca2+ buffering capacities between CA1 and DG neurons. My project will shed light on how mitochondrial diversity affects neuronal function and, ultimately, how differential neuroenergetic susceptibility can make certain neuron classes especially vulnerable to pathology-related stress.

• DFG Programme: WBP Position